- Email: [email protected]
Angiotensin II and the pathophysiology of cardiovascular remodeling
Angiotensin II and the Pathophysiology of Cardiovascular Remodeling Bryan Williams,
MD
Hypertension is associated with a number of adverse morphologic and functional changes in the cardiovascular system. These include remodeling of the left ventricle, alterations in the morphology and mechanical properties of the vasculature, and the development of endothelial dysfunction. Recent studies have shown that angiotensin II is capable of mediating these changes via its interaction with the angiotensin II type 1 receptor. These nonhemodynamic effects of angiotensin II are independent of its effect on blood pressure. Thus, elevated levels of angiotensin II may lead directly to many hypertension-associated pathologies. Recent evidence that mechanical strain, oxidized low-density lipoprotein cholesterol, and aldosterone can cause upregulation of angiotensin II type 1 receptors indicates that activation of the renin–angiotensin system is not necessary for the actions of angiotensin II to be amplified. Because the
strain on the vessel wall may be increased under conditions of hypertension, increased arterial pressure may amplify the actions of angiotensin II without a discernible increase in plasma angiotensin II levels. In both the myocardium and the peripheral vasculature, fibrosis is a major component of the remodeling that occurs in hypertension. There is substantial evidence that transforming growth factor beta-1 (TGF-1) mediates angiotensinII–induced fibrosis in patients with hypertension and in those with a variety of nephropathies. Mechanical strain also induces fibrosis in a mechanism mediated by TGF-1. This cytokine thus represents a common pathway by which angiotensin II and increased arterial pressure may induce cardiovascular fibrosis. 䊚2001 by Excerpta Medica, Inc. Am J Cardiol 2001;87(suppl):10C–17C
ngiotensin II is the primary effector molecule of the renin–angiotensin system. It is formed by the A action of angiotensin-converting enzyme on the pre-
tensin II listed above are mediated by the angiotensin II type 1 (AT1) receptor. Blockade of this receptor by angiotensin receptor antagonists thus interferes with the hormone’s promotion of vasoconstriction,8 cell growth,10 oxidation,11 fibrosis,12 and angiogenesis.8 In contrast, the action of angiotensin II at its type 2 (AT2) receptor results in effects that are beneficial in general and that oppose those mediated by the AT1 receptor.13 These activities, which include vasodilation,8 apoptosis,14 kinin production,15 inhibition of fibrosis,16 and the suppression of angiogenesis,8 may actually be enhanced by the administration of an angiotensin receptor antagonist, because angiotensin II levels tend to increase in response to AT1 blockade.17 AT1 and AT2 receptors thus appear to have a “Yin–Yang” relationship.
1
cursor molecule angiotensin I and is primarily recognized for its role in the regulation of arterial pressure and blood volume.1 This vasopressor action of angiotensin II, which can be lifesaving, may also lead to hypertension if the renin–angiotensin system is activated inappropriately.2 Moreover, among patients with hypertension, activity of the renin–angiotensin system as assessed by plasma renin levels is an independent risk factor for secondary complications.3 In addition to its pressor effect, angiotensin II has a variety of nonhemodynamic actions, many of which are associated with cardiovascular and renal pathology. For example, angiotensin-II–induced cell growth may lead to left ventricular hypertrophy and vascular remodeling.1 Angiotensin II also induces fibrosis in both the cardiovascular and renal systems,1 predisposes to endothelial dysfunction and atherosclerosis by promoting oxidative stress,4 and contributes to the formation and instability of atherosclerotic plaques.5,6 By altering glomerular permeability, it may also lead to the development of proteinuria in patients with nephropathy.7 Angiotensin II is also angiogenic8 and may be involved in the development of microangiopathy.9 Almost all the nonhemodynamic effects of angioFrom the Cardiovascular Research Institute, Leicester University Medical School, Leicester, United Kingdom. Address for reprints: Bryan Williams, MD, Cardiovascular Research Institute, Department of Medicine, Leicester University Medical School, Sir Robert Kilpatrick Critical Sciences Building, PO Box 65, Leicester Royal Infirmary, Leicester LE2 7LX, United Kingdom.
10C
©2001 by Excerpta Medica, Inc. All rights reserved.
HYPERTENSION-INDUCED CHANGES IN CARDIOVASCULAR MORPHOLOGY AND FUNCTION Hypertension is associated with a number of adverse changes in cardiovascular morphology and function. Both left ventricular hypertrophy and myocardial fibrosis are frequent sequelae of increased arterial pressure. The increase in left ventricular mass that is associated with these pathologic changes is a major risk factor not only for cardiovascular morbidity and mortality but also for all-cause mortality.18 Hypertension is also associated with changes in the structural and mechanical properties of the arteries, including a decrease in luminal diameter,19 an increase in the media/lumen ratio,19 and changes in vascular wall stiffness.20 These changes increase vascular resistance to flow, further compounding the elevation in blood pressure.20 In addition, hypertension is associated with 0002-9149/01/$ – see front matter PII S0002-9149(01)01507-7
the development of endothelial dysfunction.21 The aim of this article is to review the mechanisms by which angiotensin II mediates these hypertension-induced changes in cardiovascular morphology and function.
THE ROLE OF ANGIOTENSIN II IN HYPERTENSION-INDUCED CHANGES IN CARDIOVASCULAR MORPHOLOGY AND FUNCTION
Upregulation of the AT1 receptor: Many hypertensive individuals have no evidence of elevated plasma renin or angiotensin levels. In these cases, the involvement of the renin–angiotensin system in the pathogenesis of hypertension is controversial. One potential explanation is that activation of local tissue renin– angiotensin systems may not be reflected in plasma values. Alternatively, the effects of normal plasma levels of angiotensin II could be amplified by upregulation of AT1 receptors. Such upregulation has been shown to occur in response to a variety of stimuli. Mechanical strain: Even in normotensive individuals, the arterial wall experiences substantial mechanical strain (“stretch”) with each heartbeat. Safar et al22 demonstrated a positive relation between the diameter of the brachial artery and mean arterial pressure in a mixed group of normotensive and hypertensive subjects. The mean arterial diameter of the hypertensive group approached that of the normotensive group within 30 minutes of blood pressure normalization. Thus, in subjects with hypertension, arterial wall strain is increased in a dynamic fashion that is unrelated to vascular remodeling. Vascular smooth muscle cells are responsive to changes in strain and have been shown to hypertrophy, proliferate, undergo phenotypic shifts, and change their orientation in response to changes in this parameter.23 Stanley et al24 recently investigated the effect of strain on AT1 receptor messenger RNA (mRNA) expression in human vascular smooth muscle cells in vitro. After 3 hours of exposure to a continuous cyclical strain regime designed to mimic the forces generated by hypertension in vivo, AT1 receptor mRNA expression increased by 270%. Stanley et al24 went on to show that this increased receptor expression was functionally relevant by measuring phosphorylated p42/44 mitogen-activated kinase. This enzyme is activated by angiotensin II in vascular smooth muscle cells25 and can be used as an index of angiotensin-II–induced cellular activation. Angiotensin II alone increased kinase activity by 21%, whereas exposure of cells to cyclical strain for 10 minutes increased it by 88%. However, kinase activity was increased by 176% in cells exposed to strain before incubation with angiotensin II. Taken together, these results suggest that mechanical strain sensitizes vascular smooth muscle cells to the effects of angiotensin II by upregulating AT1 receptor expression and that this mechanism may render the vasculature of hypertensive patients hyperresponsive to the effects of angiotensin II.
Oxidized low-density lipoprotein cholesterol: The renin–angiotensin system is known to play an important role in the development of atherosclerosis.26 Among the mechanisms that may mediate this risk is angiotensin-II–induced upregulation of the endothelial cell receptor for oxidized low-density lipoprotein cholesterol.27 Upregulation of this receptor by angiotensin facilitates the uptake of oxidized low-density lipoprotein cholesterol by coronary artery endothelial cells and enhances the degree of cell injury that results.27 Li et al26 recently found further evidence of a connection between dyslipidemia and the renin–angiotensin system by demonstrating that oxidized low-density lipoprotein cholesterol upregulates AT1 expression in human coronary artery endothelial cells.26 Blockade of the AT1 receptor attenuated the injurious effects of oxidized low-density lipoprotein on endothelial cells, a finding that emphasizes the potential importance of the renin–angiotensin system in the pathogenesis of atherosclerosis.26 Aldosterone: A further mechanism by which angiotensin II may augment its own response is via aldosterone-induced upregulation of AT1 receptors. As a fundamental part of its pressor activity, angiotensin II induces the release of aldosterone by the adrenal gland.1 Investigating the mechanism of aldosteroneinduced cardiac fibrosis, Robert et al28 found that uninephrectomized rats treated with aldosterone and sodium chloride for 1 month showed a 2-fold increase in the density of AT1 receptors in the ventricles and a 3-fold increase in AT1 mRNA levels compared with sham-operated rats. Although the mechanism of this induction was not established, the fact that it was blocked by the aldosterone antagonist spironolactone suggests that it was mediated by aldosterone acting at mineralocorticoid receptors.28 Vascular remodeling and endothelial dysfunction:
The arteries of hypertensive patients undergo characteristic changes in morphology that are closely associated with alterations in vascular function.29 Changes in the small “resistance” arteries are of particular interest, because any alteration in the resistance to flow of these vessels has a substantial effect on arterial pressure.19 The structural and functional consequences of hypertension-induced remodeling have been studied extensively in these vessels. Schiffrin and Deng30 studied the effects of hypertension on the morphology of resistance arteries obtained from subcutaneous gluteal biopsies of 40 normotensive subjects and 45 subjects with untreated essential hypertension. The arteries from the hypertensive patients had a significantly higher media/lumen ratio and a smaller lumen diameter than those from the normotensive subjects. These changes are associated with a number of adverse functional consequences, including amplification of the effects of vasoconstrictors.31 Recent evidence suggests that elevated blood pressure per se may not be responsible for the vascular remodeling that occurs in hypertensive individuals. Schiffrin et al29 compared the effects of treatment with the AT1 receptor blocker losartan and the 1-selective
A SYMPOSIUM: ANGIOTENSIN II IN CARDIVOSACULAR PATHOLOGY
11C
FIGURE 1. Effect of treatment with losartan or atenolol on the media/lumen ratio of resistance arteries from patients with essential hypertension. Individual values and means ⴞ standard error are shown. One year of treatment with losartan resulted in a significant decrease in this ratio, whereas atenolol had no significant effect on this parameter. *p <0.01 versus pretreatment and versus atenolol treatment. (Adapted with permission from Circulation and Lippincott Williams & Wilkins.29)
antagonist atenolol on the characteristics of resistance arteries from patients with essential hypertension. Prior to treatment, the media/lumen ratio of arteries from the hypertensive patients was significantly higher than that of a control group of normotensive subjects. After 1 year of treatment, this ratio had decreased in all 9 patients treated with losartan, and the mean media/lumen ratio of this group was significantly decreased (Figure 1). In contrast, the atenololtreated patients (n ⫽ 10) showed a nonsignificant increase in the media/lumen ratio. Because similar reductions in systolic and diastolic blood pressure were achieved in both groups, the reduced media/ lumen ratio was evidently an effect of AT1 receptor blockade rather than of arterial pressure reduction. Another prominent feature of hypertension-induced vascular remodeling is hypertrophy of vascular smooth muscle cells.20 Angiotensin II has been shown to induce such hypertrophy in vitro,32 and recent work has shown that it does so by activating NADH/ NADPH oxidase.32 In the presence of superoxide dismutase, the superoxide formed during activation of NADH/NADPH oxidase is converted to hydrogen peroxide faster than it can be degraded by catalase.32 Using cells that overexpress catalase, Zafari et al32 showed that this increase in intracellular hydrogen peroxide level is necessary for angiotensin-II–induced hypertrophy to occur. The angiotensin-II–induced increase in peroxide level was inhibited by blockade of the AT1 receptor. Angiotensin II is thus capable of inducing vascular growth by altering the redox state of the cell in a process mediated by the AT1 receptor.32 In addition to studying the effects of losartan and atenolol on the morphology of resistance arteries from hypertensive patients, Schiffrin et al29 compared the effects of these 2 agents on endothelial dysfunction. Before treatment, resistance arteries from the hypertensive patients showed impaired endothelium-depen12C THE AMERICAN JOURNAL OF CARDIOLOGY姞
dent relaxation (ie, reduced dilatory response to acetylcholine) but were no different from control arteries in their response to sodium nitroprusside, an agent that produces endothelium-independent relaxation. The response to acetylcholine was normalized after 1 year of treatment with losartan but remained essentially unchanged after treatment with atenolol (Figure 2). Endothelium-independent relaxation was not affected by either treatment. These studies thus demonstrated that both the morphologic changes and the endothelial dysfunction seen in resistance arteries of hypertensive patients are reversed by AT1 receptor blockade. The fact that these parameters are unaffected by reduction in arterial pressure demonstrates that this is a specific effect of angiotensin II acting at the AT1 receptor. Mechanical properties of the vasculature: In addition to being associated with changes in the structure and function of small arteries, hypertension may also result in changes in the mechanical properties of arterial walls. Although it is generally assumed that hypertension leads to an increase in arterial wall stiffness, this has not been a universal finding, and reports of reduced33 and unchanged34 arterial wall stiffness have also been published. Some of these inconsistencies may be related to the vascular bed under study,35 the parameter used to determine stiffness (eg, compliance and distensibility are to some extent dependent on the geometry of the vessel),20 and the chronicity of the hypertension.20 Park et al20 recently compared the effects of losartan and atenolol on the stiffness of small subcutaneous gluteal arteries in patients with essential hypertension. A geometry-independent measure of arterial wall stiffness was used (slope of the elastic modulus vs stress). After 1 year of treatment, arterial wall stiffness was significantly reduced in the losartan-treated patients but remained unchanged in the atenolol-treated patients (Figure 3). Because the 2 drugs produced sim-
VOL. 87 (8A)
APRIL 19, 2001
FIGURE 2. Effect of treatment with losartan or atenolol on endothelium-dependent (acetylcholine) relaxation of resistance arteries from patients with essential hypertension. Before treatment, both groups of hypertensive patients showed an abnormally reduced dilatory response to acetylcholine. This was normalized by treatment with losartan but not by atenolol. *p <0.05 versus normotensive group. †p <0.05 versus losartan group before treatment and versus atenolol group after treatment. (Adapted with permission from Circulation and Lippincott Williams & Wilkins.29)
FIGURE 3. Effect of treatment with losartan or atenolol on stiffness of resistance arteries from patients with essential hypertension. The slope of the plot of incremental elastic modulus (a geometry-independent measurement of arterial wall stiffness) versus stress was measured before and after treatment with losartan or atenolol. After 1 year of treatment, arteries from the losartan-treated patients showed a significant reduction in wall stiffness, whereas those from atenolol-treated patients did not. *p <0.05 versus “losartan before” measurement. (Reprinted with permission from JRAAS.20)
ilar reductions in blood pressure, this change in stiffness appears to be a direct effect of angiotensin II acting at the AT1 receptor. The reduction in stiffness reported by Park et al20 was associated with a reduction in the media/lumen ratio.29 Angiotensin receptor antagonists are known to inhibit hypertension-induced vascular fibrosis,36 and Park et al20 suggested that the losartan-induced change in mechanical properties may have been mediated by a reduction in the collagen content of the media layer of the vessels. Left ventricular remodeling: An increase in left ventricular mass is a common consequence of hypertension. This condition, often loosely termed left ventric-
ular hypertrophy, is characterized by increases in extracellular matrix (myocardial fibrosis) as well as in myocyte size (true hypertrophy).37 The fibrosis induced by hypertension can be extensive. For example, Querejeta et al38 found that the collagen volume fraction of hearts from individuals with no evidence of cardiovascular disease was 1.95 ⫾ 0.07% (mean ⫾ SEM, range of values 1.39% to 2.15%, n ⫽ 10). In contrast, the collagen volume fraction of 26 hearts from hypertensive patients was 5.23 ⫾ 0.38% (range 2.08% to 9.83%, p ⬍0.001). Because many studies do not distinguish between the contributions of fibrosis and myocyte hypertrophy to hypertension-induced
A SYMPOSIUM: ANGIOTENSIN II IN CARDIVOSACULAR PATHOLOGY
13C
ventricular remodeling, these 2 pathologies will be discussed together. Remodeling of the left ventricle may ultimately lead to systolic dysfunction and cardiac failure.37 Activation of the renin–angiotensin system may contribute to the increase in left ventricular mass seen during hypertension. In vitro, angiotensin II induces hypertrophy of cardiac myocytes and causes cardiac fibroblasts to accumulate collagen.1,10,12 In vivo, angiotensin II induces myocardial collagen deposition, myocyte hypertrophy, and increased left ventricular mass.1,10,12 These effects are all mediated by the AT1 receptor.1,10,12 Both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been shown to prevent and reverse hypertension-induced increases in left ventricular mass and collagen deposition in a variety of murine models of hypertension.1,10,12 For example, Ikeda et al39 treated stroke-prone spontaneously hypertensive rats with the AT1 receptor antagonist candesartan, the angiotensin-converting enzyme inhibitor captopril, or hydralazine, an antihypertensive agent that does not affect the renin–angiotensin system. Treatment was started at 12 weeks of age, by which time the rats had already developed substantial left ventricular hypertrophy. At 24 weeks of age, untreated spontaneously hypertensive rats had decreased coronary reserve, left ventricular hypertrophy, increased myocyte size, and increased interstitial collagen volume fraction. In contrast, in spontaneously hypertensive rats treated from 12 to 24 weeks of age with captopril or candesartan, measurements of left ventricular weight, myocyte size, and interstitial collagen volume fraction were all similar to those of normal control animals. Treatment with hydralazine decreased the collagen volume fraction, but this was the only measure of cardiac remodeling on which it had a positive effect. Similar results were obtained by Yamazaki and Yazaki,40 who treated spontaneously hypertensive rats with candesartan or hydralazine. Left ventricular weight, left ventricular wall thickness, transverse myocyte diameter, and the amount of interstitial fibrosis were all lower in the candesartan-treated rats than in untreated controls. Treatment with hydralazine had a small effect on the increase in left ventricular wall thickness but no significant effect on the other parameters. The results of these 2 studies39,40 suggest that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers prevent hypertension-induced cardiac remodeling by interacting with the AT1 receptor and that this effect is not mediated by changes in arterial pressure. In humans, reducing the activity of the renin– angiotensin system is a more effective method of reversing hypertension-induced left ventricular remodeling than diuresis, -receptor blockade, or calcium channel blockade. In a meta-analysis of 109 studies, Dahlo¨f et al41 calculated the reduction in left ventricular mass achieved by angiotensin-converting enzyme inhibitors, calcium antagonists, -blockers, and thiazide diuretics. When the data were examined 14C THE AMERICAN JOURNAL OF CARDIOLOGY姞
using the same formula for all studies, the reductions in mass achieved by these 4 drug classes were 16%, 10%, 9%, and 8%, respectively. Overall, there was a significant correlation between the reductions in left ventricular mass and mean arterial pressure, but this relation still explained only 29% of the reduction in mass. When the reduction in left ventricular mass was expressed as a function of the reduction in mean arterial pressure, angiotensin-converting enzyme inhibitors were superior to the other 3 drug classes with an average reduction in mass of 2.3 g/mm Hg reduction in pressure (Figure 4).41 Calcium antagonists achieved an average reduction of 1.4 g/mm Hg; thiazide diuretics, 1.1 g/mm Hg; and -blockers, 0.9 g/mm Hg. A recent meta-analysis that used more stringent inclusion criteria and a smaller number of clinical trials (n ⫽ 39)42 confirmed the superiority of angiotensin-converting enzyme inhibitors over other antihypertensive medications for reducing left ventricular mass. Data from human clinical trials also suggest that angiotensin II, acting through the AT1 receptor, is involved in the production of left ventricular hypertrophy. For example, losartan has been shown to reduce left ventricular mass in hypertensive patients43,44 and is substantially more effective than the thiazide diuretic hydrochlorothiazide in this regard.43
ANGIOTENSIN-II–INDUCED CARDIOVASCULAR FIBROSIS MAY BE MEDIATED BY TGF-1
Transforming growth factor-1 (TGF-1) is known to be important in the regulation of extracellular matrix production, and overproduction of this agent is associated with fibrogenesis.45 There is growing evidence that the fibrosis induced by angiotensin II may be mediated by this cytokine.12,46 For example, Kagami et al47 showed that rat mesangial cells respond to treatment with angiotensin II by increasing the synthesis of TGF-1 mRNA, TGF-1 protein, and various components of the extracellular matrix, including type I collagen. Coincubation of the cells with angiotensin II and neutralizing antibody to TGF-1 blocked the angiotensin-II–induced synthesis of extracellular matrix components, suggesting that the fibrotic response of mesangial cells to angiotensin II is dependent on TGF-1. The association between angiotensin II, TGF-1, and fibrosis is also apparent in vivo. In various murine models of vascular disease, including hypertension, the reduction in cardiovascular hypertrophy and extracellular matrix production that results from administration of an angiotensin receptor blocker is accompanied by suppressed production of TGF-1 and collagen types I, III, and IV.1 This suggests that the association between angiotensin II, TGF-1, and fibrosis is mediated by the AT1 receptor. There is growing evidence that various forms of nephropathy and hypertension-induced pathology in humans may be jointly mediated by TGF-1 and angiotensin II. Suthanthiran et al48 showed that serum TGF-1 levels are significantly higher in hypertensive
VOL. 87 (8A)
APRIL 19, 2001
FIGURE 4. Results of a meta-analysis of the effects of 4 antihypertensive treatments on calculated left ventricular mass, normalized to the reduction in mean arterial pressure. Angiotensinconverting enzyme inhibitors achieved a greater reduction in left ventricular mass per mm Hg reduction in mean arterial pressure than did -blockers, thiazide diuretics, or calcium antagonists. ACE ⴝ angiotensin-converting enzyme; CCB ⴝ calcium channel blocker; LV ⴝ left ventricle; MAP ⴝ mean arterial pressure. (Data from Am J Hypertens.41)
individuals than in those with normal blood pressure. In addition, within both normotensive and hypertensive populations, black individuals had higher TGF-1 levels than white individuals did.48 This ethnic difference is of interest because blacks not only have higher rates of hypertension than whites do49 but also have a higher incidence of conditions commonly associated with hypertension such as left ventricular hypertrophy,50 ischemic stroke,51 and end-stage renal disease.52 TGF-1 levels have been shown to correlate with blood pressure in patients with end-stage renal disease,53 and blacks with this disease have higher TGF-1 levels than whites do.54 Recent work in human patients with various forms of nephropathy has shown that the beneficial clinical effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be mediated by reductions in TGF-1 expression. For example, Nishimura et al55 studied the effects of treatment with angiotensin-converting enzyme inhibitors on the level of TGF-1 mRNA in renal biopsies from patients with IgA nephropathy. Although patients treated with angiotensin-converting enzyme inhibitors had a worse initial prognosis (based on factors such as disease duration and degree of proteinuria), the level of TGF-1 mRNA in these patients was only 60% of the level in untreated patients at the end of the study. Sharma et al56 measured serum levels of TGF-1 in patients with diabetic nephropathy before and after 6 months of treatment with placebo or with the angiotensin-converting enzyme inhibitor captopril. Over this 6-month period, TGF-1 levels increased by 11% in the placebo group (p ⫽ 0.003) and decreased by 14% in the captopril group (p ⫽ 0.01). In both groups of patients, the percent change in TGF-1 level during this 6-month period showed a significant inverse correlation with the percent change in glomerular filtration rate that occurred in the ensuing 2 years. This
correlation was strongest (r ⫽ ⫺0.73, p ⫽ 0.0001) in captopril-treated patients with renal insufficiency at baseline (glomerular filtration rate ⬍75 mL/min). Changes in serum creatinine, mean arterial pressure, proteinuria, and glycosylated hemoglobin were not predictive of the change in glomerular filtration rate. Sharma et al56 did not determine the mechanism by which captopril elicited these beneficial changes in TGF-1 level and renal function. However, work by Campistol et al57 strongly suggests that reduced stimulation of the AT1 receptor is involved. These authors measured plasma TGF-1 levels in patients with chronic allograft nephropathy before and after treatment with the angiotensin receptor blocker losartan. TGF-1 has been implicated in the pathogenesis of chronic renal allograft dysfunction.58 Before treatment, this cytokine was present at higher levels in the patients with nephropathy than in a control group of transplant patients with normal renal function. Losartan significantly decreased TGF-1 levels, and the decrease in TGF-1 was correlated with blockade of the angiotensin II receptor. This finding suggests that binding of the AT1 receptor initiates TGF-1 synthesis. One reason that the roles of angiotensin II and TGF-1 have been studied so extensively in models of nephropathy is that the kidney is particularly susceptible to TGF-1–induced fibrosis.45 However, there is also evidence that TGF-1 plays a role in the cardiovascular remodeling induced by hypertension. Villarreal and Dillmann59 showed that TGF-1 mRNA increased within 12 hours of the onset of experimental pressure overload and that this increase preceded increased expression of extracellular matrix proteins and cardiac hypertrophy. Everett et al60 studied the effect of AT1 receptor blockade on the cardiac hypertrophy induced by coarctation of the aorta. In rats that received no pharmacologic treatment after coarctation,
A SYMPOSIUM: ANGIOTENSIN II IN CARDIVOSACULAR PATHOLOGY
15C
the development of cardiac hypertrophy (defined as an increase in the heart weight to body weight ratio) was associated with a 2-fold increase in TGF-1 mRNA levels.60 In contrast, animals treated with losartan after coarctation demonstrated neither cardiac hypertrophy nor elevated TGF-1 levels. Further evidence for a link between TGF-1, angiotensin II, and cardiac fibrosis comes from work carried out using a rat model of nitric oxide synthase inhibition. Tomita et al61 showed that the cardiac fibrosis that is induced in this model is preceded by increases in cardiac TGF-1 and extracellular matrix protein mRNA levels. TGF-1 immunoreactivity was increased in areas of fibrosis.61 Administration of an angiotensin II type 1 receptor antagonist, but not hydralazine, prevented both the cardiac fibrosis and the increased TGF-1 and extracellular matrix protein expression. Tomita et al61 also demonstrated that administration of a neutralizing antibody against TGF-1 did not prevent the increase in TGF-1 mRNA levels but did prevent the increase in extracellular matrix protein mRNA levels. Thus, in this model, angiotensin-II–induced TGF-1 production plays a major role in the development of cardiac fibrosis.
TGF-1 MAY REPRESENT A COMMON PATHWAY FOR ANGIOTENSIN-II–INDUCED AND STRAIN-INDUCED CARDIOVASCULAR FIBROSIS In both mesangial and vascular smooth muscle cells, mechanical strain increases TGF-1 mRNA and protein synthesis, and induces elaboration of extracellular matrix.62,63 In both of these cell types, the straininduced increase in extracellular matrix protein synthesis is inhibited by the presence of neutralizing or blocking antibodies to TGF-1.62,63 Because the strain to which cardiovascular tissues are exposed may be increased by increased arterial pressure,22 these data imply that the increased extracellular matrix synthesis and cardiovascular fibrosis that occur in response to hypertension may be mediated, at least in part, by strain-induced increases in TGF-1 levels. As discussed above, TGF-1 expression can also be induced by angiotensin II acting at the AT1 receptor. Strain-induced and angiotensin-II–induced cardiovascular fibrosis may therefore proceed by the same mechanism. In hypertensive patients in whom both arterial strain and angiotensin II levels are elevated, these pathways may constitute a dual mechanism whereby cardiovascular fibrosis is accelerated.
CONCLUSION Angiotensin II is widely involved in the pathogenesis of hypertension-induced changes in cardiovascular morphology and function. In addition to causing elevated arterial pressure per se, angiotensin II is also involved in detrimental changes in vascular morphology, endothelial function, and vessel wall stiffness, and induces left ventricular hypertrophy and myocar16C THE AMERICAN JOURNAL OF CARDIOLOGY姞
dial fibrosis. These actions are mediated by the AT1 receptor. The finding that mechanical strain induces upregulation of the AT1 receptor suggests that the pathologic changes in the vasculature associated with hypertension may result from sensitization of vascular smooth muscle cells to angiotensin II. Angiotensin II receptor blockade may thus allow hypertensive individuals to avoid many of the consequences of the disease, including the systolic dysfunction that results from left ventricular remodeling, and the end-stage renal failure that afflicts so many hypertensive patients.
1. Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated
cardiovascular and renal diseases. Pharmacol Rev 2000;52:11–34. 2. Seravalle G, Cattaneo BM, Giannattasio C, Perondi R, Saino A, Grassi G,
Mancia G. RAA system and cardiovascular control in normal subjects, hypertensives and patients with congestive heart failure. J Hum Hypertens 1993; 7(suppl 2):S13–18. 3. Alderman MH, Madhavan S, Ooi WL, Cohen H, Sealey JE, Laragh JH. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med 1991;324:1098 –1104. 4. Warnholtz A, Nickenig G, Schulz E, Macharzina R, Bra¨sen JH, Skatchkov M, Heitzer T, Stasch JP, Griendling KK, Harrison DG, et al. Increased NADHoxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system. Circulation 1999;99: 2027–2033. 5. Pratt RE. Angiotensin II and the control of cardiovascular structure. J Am Soc Nephrol 1999;10:S120 –S128. 6. Schieffer B, Schieffer E, Hilfiker-Kleiner D, Hilfiker A, Kovanen PT, Kaartinen M, Nussberger J, Harringer W, Drexler H. Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability. Circulation 2000;101:1372–1378. 7. Remuzzi A, Perico N, Sangalli F, Vendramin G, Moriggi M, Ruggenenti P, Remuzzi G. ACE inhibition and ANG II receptor blockade improve glomerular size-selectivity in IgA nephropathy. Am J Physiol 1999;276:F457–F466. 8. Munzenmaier DH, Greene AS. Opposing actions of angiotensin II on microvascular growth and arterial blood pressure. Hypertension 1996;27:760 –765. 9. Williams B. A potential role for angiotensin II-induced vascular endothelial growth factor expression in the pathogenesis of diabetic nephropathy? Miner Electrolyte Metab 1998;24:400 – 405. 10. Lijnen P, Petrov V. Antagonism of the renin-angiotensin system, hypertrophy and gene expression in cardiac myocytes. Methods Find Exp Clin Pharmacol 1999;21:363–374. 11. Rajagopalan S, Kurz S, Mu¨nzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Invest 1996;97:1916 –1923. 12. Lijnen P, Petrov V. Antagonism of the renin-angiotensin-aldosterone system and collagen metabolism in cardiac fibroblasts. Methods Find Exp Clin Pharmacol 1999;21:215–227. 13. Carey RM, Wang Z-Q, Siragy HM. Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function. Hypertension 2000;35: 155–163. 14. Gallinat S, Busche S, Raizada MK, Sumners C. The angiotensin II type 2 receptor: an enigma with multiple variations. Am J Physiol Endocrinol Metab 2000;278:E357–E374. 15. Tsutsumi Y, Matsubara H, Masaki H, Kurihara H, Murasawa S, Takai S, Miyazaki M, Nozawa Y, Ozono R, Nakagawa K, et al. Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation. J Clin Invest 1999;104:925–935. 16. Morrissey JJ, Klahr S. Effect of AT2 receptor blockade on the pathogenesis of renal fibrosis. Am J Physiol 1999;276:F39 –F45. 17. Campbell DJ, Kladis A, Valentijn AJ. Effects of losartan on angiotensin and bradykinin peptides and angiotensin-converting enzyme. J Cardiovasc Pharmacol 1995;26:233–240. 18. Koren MJ, Devereuz RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991;114:345–352. 19. Schiffrin EL. Reactivity of small blood vessels in hypertension: relation with structural changes. State of the art lecture. Hypertension 1992;19(suppl II):II-1– II-9. 20. Park JB, Intengan HD, Schiffrin EL. Reduction of resistance artery stiffness by treatment with the AT1-receptor antagonist losartan in essential hypertension. JRAAS 2000;1:40 – 45. 21. Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. Abnormal endotheliumdependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990;323:22–27.
VOL. 87 (8A)
APRIL 19, 2001
22. Safar ME, Peronneau PA, Levenson JA, Toto-Moukouo JA, Simon AC. Pulsed Doppler: diameter, blood flow velocity, and volumic flow of the brachial artery in sustained essential hypertension. Circulation 1981;63:393– 400. 23. Williams B. Mechanical influences on vascular smooth muscle cell function. J Hypertens 1998;16:1921–1929. 24. Stanley AG, Knight AL, Williams B. Mechanical strain sensitizes human vascular smooth muscle cells to angiotensin II [abstract]. Am J Hypertens 2000; 13:12A. 25. Liao D-F, Duff JL, Daum G, Pelech SL, Berk BC. Angiotensin II stimulates MAP kinase kinase kinase activity in vascular smooth muscle cells: role of Raf. Circ Res 1996;79:1007–1014. 26. Li D, Saldeen T, Romeo F, Mehta JL. Oxidized LDL upregulates angiotensin II type 1 receptor expression in cultured human coronary artery endothelial cells: the potential role of transcription factor NF-B. Circulation 2000;102:1970 – 1976. 27. Li DY, Zhang YC, Philips MI, Sawamura T, Mehta JL. Upregulation of endothelial receptor for oxidized low-density lipoprotein (LOX-1) in cultured human coronary artery endothelial cells by angiotensin II type 1 receptor activation. Circ Res 1999;84:1043–1049. 28. Robert V, Heymes C, Silvestre J-S, Sabri A, Swynghedauw B, Delcayre C. Angiotensin AT1 receptor subtype as a cardiac target of aldosterone: role in aldosterone-salt-induced fibrosis. Hypertension 1999;33:981–986. 29. Schiffrin EL, Park JB, Intengan HD, Touyz RM. Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan. Circulation 2000;101:1653–1659. 30. Schiffrin EL, Deng LY. Relationship between small-artery structure and systolic, diastolic and pulse pressure in essential hypertension. J Hypertens 1999;17:381–387. 31. Deng LY, Schiffrin EL. Effects of endothelin-1 and vasopressin on resistance arteries of spontaneously hypertensive rats. Am J Hypertens 1992;5:817– 822. 32. Zafari AM, Ushio-Fukai M, Akers M, Yin Q, Shah A, Harrison DG, Taylor WR, Griendling KK. Role of NADH/NADPH oxidase-derived H2O2 in angiotensin II-induced vascular hypertrophy. Hypertension 1998;32:488 – 495. 33. Intengan HD, Deng LY, Li JS, Schiffrin EL. Mechanics and composition of human subcutaneous resistance arteries in essential hypertension. Hypertension 1999;33:569 –574. 34. Thybo NK, Mulvany MJ, Jastrup B, Nielsen H, Aalkjaer C. Some pharmacological and elastic characteristics of isolated subcutaneous small arteries from patients with essential hypertension. J Hypertens 1996;14:993–998. 35. Safar ME, London GM. Arterial stiffness in hypertensive subjects with or without end-stage renal disease. Kidney Blood Press Res 1997;20:82– 89. 36. Kim S, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K, Inada Y, Ishimura Y, Chatani F, Iwao H. Angiotensin II type 1 receptor antagonist inhibits the gene expression of transforming growth factor-1 and extracellular matrix in cardiac and vascular tissues of hypertensive rats. J Pharmacol Exp Ther 1995; 273:509 –515. 37. Brilla CG, Maisch B. Regulation of the structural remodelling of the myocardium: from hypertrophy to heart failure. Eur Heart J 1994:15(suppl D):45–52. 38. Querejeta R, Varo N, Lo´pez B, Larman M, Artin˜ano E, Etayo JC, Martı´nez Ubago JLM, Gutierrez-Stampa M, Emparanza JI, Gil MJ, et al. Serum carboxyterminal propeptide of procollagen type 1 is a marker of myocardial fibrosis in hypertensive heart disease. Circulation 2000;101:1729 –1735. 39. Ikeda Y, Nakamura T, Takano H, Kimura H, Obata J-E, Takeda S, Hata A, Shido K, Mochizuki S, Yoshida Y. Angiotensin II-induced cardiomyocyte hypertrophy and cardiac fibrosis in stroke-prone spontaneously hypertensive rats. J Lab Clin Med 2000;135:353–359. 40. Yamazaki T, Yazaki Y. Role of tissue angiotensin II in myocardial remodeling induced by mechanical stress. J Hum Hypertens 1999;13(suppl 1):S43– 47. 41. Dahlo¨f B, Pennert K, Hansson L. Reversal of left ventricular hypertrophy in hypertensive patients: a metaanalysis of 109 treatment studies. Am J Hypertens 1992;5:95–110. 42. Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension: a meta-analysis of randomized double-blind studies. JAMA 1996;275:1507–1513. 43. Tedesco MA, Ratti G, Aquino D, Limongelli G, Di Salvo G, Mennella S, Galzerano D, Iarussi D, Iacono A. Effects of losartan on hypertension and left ventricular mass: a long-term study. J Hum Hypertens 1998;12:505–510.
44. Avanza AC Jr, El Aouar LM, Mill JG. Reduction in left ventricular hyper-
trophy in hypertensive patients treated with enalapril, losartan or the combination of enalapril and losartan [in Portuguese]. Arq Bras Cardiol 2000;74:111–117. 45. Border WA, Noble NA. Interactions of transforming growth factor- and angiotensin II in renal fibrosis. Hypertension 1998;31:181–188. 46. Weber KT, Swamynathan SK, Guntaka RV, Sun Y. Angiotensin II and extracellular matrix homeostasis. Int J Biochem Cell Biol 1999;31:395– 403. 47. Kagami S, Border WA, Miller DE, Noble NA. Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor- expression in rat glomerular mesangial cells. J Clin Invest 1994;93: 2431–2437. 48. Suthanthiran M, Li B, Song JO, Ding R, Sharma VK, Schwartz JE, August P. Transforming growth factor-1 hyperexpression in African-American hypertensives: a novel mediator of hypertension and/or target organ damage. Proc Natl Acad Sci U S A 2000;97:3479 –3484. 49. Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, Horan MJ, Labarthe D. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension 1995;25:305–313. 50. Taylor JO, Borhani NO, Entwisle G, Farber M, Hawkins CM, on behalf of the HDFP Cooperative Group. Summary of the baseline characteristics of the hypertensive participants. Hypertension 1983;5(suppl IV):IV-44 –IV-50. 51. Rosamond WD, Folsom AR, Chambless LE, Wang C-H, McGovern PG, Howard G, Copper LS, Shahar E. Stroke incidence and survival among middleaged adults: 9-year follow-up of the Atherosclerosis Risk in Communities (ARIC) cohort. Stroke 1999;30:736 –743. 52. Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, Stamler J. End-stage renal disease in African-American and white men: 16-year MRFIT findings. JAMA 1997;277:1293–1298. 53. Li B, Khanna A, Sharma V, Singh T, Suthanthiran M, August P. TGF-1 DNA polymorphisms, protein levels, and blood pressure. Hypertension 1999b; 33:271–275. 54. Suthanthiran M, Khanna A, Cukran D, Adhikarla R, Sharma VK, Singh T, August P. Tranforming growth factor-1 hyperexpression in African American end-stage renal disease patients. Kidney Int 1998;53:639 – 644. 55. Nishimura M, Okamura M, Konishi Y, Inoue K, Young CK, Yoshioka T, Negoro N, Inoue T, Kanayama Y. Effect of treatment with ACE inhibitor (ACEI) on TGF-beta gene expressions in renal biopsy from patients with IgA nephropathy [abstract]. J Am Soc Nephrol 1995;6:397. 56. Sharma K, Eltayeb BO, McGowan TA, Dunn SR, Alzahabi B, Rohde R, Ziyadeh FN, Lewis EJ. Captopril-induced reduction of serum levels of transforming growth factor-1 correlates with long-term renoprotection in insulindependent diabetic patients. Am J Kidney Dis 1999;34:818 – 823. 57. Campistol JM, Inigo P, Jimenez W, Lario S, Clesca PH, Oppenheimer F, Rivera F. Losartan decreases plasma levels of TGF-1 in transplant patients with chronic allograft nephropathy. Kidney Int 1999;56:714 –719. 58. Horvath LZ, Friess H, Schilling M, Borisch B, Deflorin J, Gold LI, Korc M, Buchler MW. Altered expression of transforming growth factor-s in chronic renal rejection. Kidney Int 1996;50:489 – 498. 59. Villarreal FJ, Dillmann WH. Cardiac hypertrophy-induced changes in mRNA levels for TGF-1, fibronectin, and collagen. Am J Physiol 1992;262:H1861– H1866. 60. Everett AD, Tufro-McReddie A, Fisher A, Gomez RA. Angiotensin receptor regulates cardiac hypertrophy and transforming growth factor-1 expression. Hypertension 1994;23:587–592. 61. Tomita H, Egashira K, Ohara Y, Takemoto M, Koyanagi M, Katoh M, Yamamoto H, Tamaki K, Shimokawa H, Takeshita A. Early induction of transforming growth factor- via angiotensin II type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats. Hypertension 1998;32:273–279. 62. Hirakata M, Kaname S, Chung U-G, Joki N, Hori Y, Noda M, Takuwa Y, Okazaki T, Fujita T, Katoh T, Kurokawa K. Tyrosine kinase dependent expression of TGF- induced by stretch in mesangial cells. Kidney Int 1997;51:1028 – 1036. 63. O’Callaghan CJ, Williams B. Mechanical strain-induced extracellular matrix production by human vascular smooth muscle cells: role of TGF-1. Hypertension 2000;36:319 –324.
A SYMPOSIUM: ANGIOTENSIN II IN CARDIVOSACULAR PATHOLOGY
17C
MD
Hypertension is associated with a number of adverse morphologic and functional changes in the cardiovascular system. These include remodeling of the left ventricle, alterations in the morphology and mechanical properties of the vasculature, and the development of endothelial dysfunction. Recent studies have shown that angiotensin II is capable of mediating these changes via its interaction with the angiotensin II type 1 receptor. These nonhemodynamic effects of angiotensin II are independent of its effect on blood pressure. Thus, elevated levels of angiotensin II may lead directly to many hypertension-associated pathologies. Recent evidence that mechanical strain, oxidized low-density lipoprotein cholesterol, and aldosterone can cause upregulation of angiotensin II type 1 receptors indicates that activation of the renin–angiotensin system is not necessary for the actions of angiotensin II to be amplified. Because the
strain on the vessel wall may be increased under conditions of hypertension, increased arterial pressure may amplify the actions of angiotensin II without a discernible increase in plasma angiotensin II levels. In both the myocardium and the peripheral vasculature, fibrosis is a major component of the remodeling that occurs in hypertension. There is substantial evidence that transforming growth factor beta-1 (TGF-1) mediates angiotensinII–induced fibrosis in patients with hypertension and in those with a variety of nephropathies. Mechanical strain also induces fibrosis in a mechanism mediated by TGF-1. This cytokine thus represents a common pathway by which angiotensin II and increased arterial pressure may induce cardiovascular fibrosis. 䊚2001 by Excerpta Medica, Inc. Am J Cardiol 2001;87(suppl):10C–17C
ngiotensin II is the primary effector molecule of the renin–angiotensin system. It is formed by the A action of angiotensin-converting enzyme on the pre-
tensin II listed above are mediated by the angiotensin II type 1 (AT1) receptor. Blockade of this receptor by angiotensin receptor antagonists thus interferes with the hormone’s promotion of vasoconstriction,8 cell growth,10 oxidation,11 fibrosis,12 and angiogenesis.8 In contrast, the action of angiotensin II at its type 2 (AT2) receptor results in effects that are beneficial in general and that oppose those mediated by the AT1 receptor.13 These activities, which include vasodilation,8 apoptosis,14 kinin production,15 inhibition of fibrosis,16 and the suppression of angiogenesis,8 may actually be enhanced by the administration of an angiotensin receptor antagonist, because angiotensin II levels tend to increase in response to AT1 blockade.17 AT1 and AT2 receptors thus appear to have a “Yin–Yang” relationship.
1
cursor molecule angiotensin I and is primarily recognized for its role in the regulation of arterial pressure and blood volume.1 This vasopressor action of angiotensin II, which can be lifesaving, may also lead to hypertension if the renin–angiotensin system is activated inappropriately.2 Moreover, among patients with hypertension, activity of the renin–angiotensin system as assessed by plasma renin levels is an independent risk factor for secondary complications.3 In addition to its pressor effect, angiotensin II has a variety of nonhemodynamic actions, many of which are associated with cardiovascular and renal pathology. For example, angiotensin-II–induced cell growth may lead to left ventricular hypertrophy and vascular remodeling.1 Angiotensin II also induces fibrosis in both the cardiovascular and renal systems,1 predisposes to endothelial dysfunction and atherosclerosis by promoting oxidative stress,4 and contributes to the formation and instability of atherosclerotic plaques.5,6 By altering glomerular permeability, it may also lead to the development of proteinuria in patients with nephropathy.7 Angiotensin II is also angiogenic8 and may be involved in the development of microangiopathy.9 Almost all the nonhemodynamic effects of angioFrom the Cardiovascular Research Institute, Leicester University Medical School, Leicester, United Kingdom. Address for reprints: Bryan Williams, MD, Cardiovascular Research Institute, Department of Medicine, Leicester University Medical School, Sir Robert Kilpatrick Critical Sciences Building, PO Box 65, Leicester Royal Infirmary, Leicester LE2 7LX, United Kingdom.
10C
©2001 by Excerpta Medica, Inc. All rights reserved.
HYPERTENSION-INDUCED CHANGES IN CARDIOVASCULAR MORPHOLOGY AND FUNCTION Hypertension is associated with a number of adverse changes in cardiovascular morphology and function. Both left ventricular hypertrophy and myocardial fibrosis are frequent sequelae of increased arterial pressure. The increase in left ventricular mass that is associated with these pathologic changes is a major risk factor not only for cardiovascular morbidity and mortality but also for all-cause mortality.18 Hypertension is also associated with changes in the structural and mechanical properties of the arteries, including a decrease in luminal diameter,19 an increase in the media/lumen ratio,19 and changes in vascular wall stiffness.20 These changes increase vascular resistance to flow, further compounding the elevation in blood pressure.20 In addition, hypertension is associated with 0002-9149/01/$ – see front matter PII S0002-9149(01)01507-7
the development of endothelial dysfunction.21 The aim of this article is to review the mechanisms by which angiotensin II mediates these hypertension-induced changes in cardiovascular morphology and function.
THE ROLE OF ANGIOTENSIN II IN HYPERTENSION-INDUCED CHANGES IN CARDIOVASCULAR MORPHOLOGY AND FUNCTION
Upregulation of the AT1 receptor: Many hypertensive individuals have no evidence of elevated plasma renin or angiotensin levels. In these cases, the involvement of the renin–angiotensin system in the pathogenesis of hypertension is controversial. One potential explanation is that activation of local tissue renin– angiotensin systems may not be reflected in plasma values. Alternatively, the effects of normal plasma levels of angiotensin II could be amplified by upregulation of AT1 receptors. Such upregulation has been shown to occur in response to a variety of stimuli. Mechanical strain: Even in normotensive individuals, the arterial wall experiences substantial mechanical strain (“stretch”) with each heartbeat. Safar et al22 demonstrated a positive relation between the diameter of the brachial artery and mean arterial pressure in a mixed group of normotensive and hypertensive subjects. The mean arterial diameter of the hypertensive group approached that of the normotensive group within 30 minutes of blood pressure normalization. Thus, in subjects with hypertension, arterial wall strain is increased in a dynamic fashion that is unrelated to vascular remodeling. Vascular smooth muscle cells are responsive to changes in strain and have been shown to hypertrophy, proliferate, undergo phenotypic shifts, and change their orientation in response to changes in this parameter.23 Stanley et al24 recently investigated the effect of strain on AT1 receptor messenger RNA (mRNA) expression in human vascular smooth muscle cells in vitro. After 3 hours of exposure to a continuous cyclical strain regime designed to mimic the forces generated by hypertension in vivo, AT1 receptor mRNA expression increased by 270%. Stanley et al24 went on to show that this increased receptor expression was functionally relevant by measuring phosphorylated p42/44 mitogen-activated kinase. This enzyme is activated by angiotensin II in vascular smooth muscle cells25 and can be used as an index of angiotensin-II–induced cellular activation. Angiotensin II alone increased kinase activity by 21%, whereas exposure of cells to cyclical strain for 10 minutes increased it by 88%. However, kinase activity was increased by 176% in cells exposed to strain before incubation with angiotensin II. Taken together, these results suggest that mechanical strain sensitizes vascular smooth muscle cells to the effects of angiotensin II by upregulating AT1 receptor expression and that this mechanism may render the vasculature of hypertensive patients hyperresponsive to the effects of angiotensin II.
Oxidized low-density lipoprotein cholesterol: The renin–angiotensin system is known to play an important role in the development of atherosclerosis.26 Among the mechanisms that may mediate this risk is angiotensin-II–induced upregulation of the endothelial cell receptor for oxidized low-density lipoprotein cholesterol.27 Upregulation of this receptor by angiotensin facilitates the uptake of oxidized low-density lipoprotein cholesterol by coronary artery endothelial cells and enhances the degree of cell injury that results.27 Li et al26 recently found further evidence of a connection between dyslipidemia and the renin–angiotensin system by demonstrating that oxidized low-density lipoprotein cholesterol upregulates AT1 expression in human coronary artery endothelial cells.26 Blockade of the AT1 receptor attenuated the injurious effects of oxidized low-density lipoprotein on endothelial cells, a finding that emphasizes the potential importance of the renin–angiotensin system in the pathogenesis of atherosclerosis.26 Aldosterone: A further mechanism by which angiotensin II may augment its own response is via aldosterone-induced upregulation of AT1 receptors. As a fundamental part of its pressor activity, angiotensin II induces the release of aldosterone by the adrenal gland.1 Investigating the mechanism of aldosteroneinduced cardiac fibrosis, Robert et al28 found that uninephrectomized rats treated with aldosterone and sodium chloride for 1 month showed a 2-fold increase in the density of AT1 receptors in the ventricles and a 3-fold increase in AT1 mRNA levels compared with sham-operated rats. Although the mechanism of this induction was not established, the fact that it was blocked by the aldosterone antagonist spironolactone suggests that it was mediated by aldosterone acting at mineralocorticoid receptors.28 Vascular remodeling and endothelial dysfunction:
The arteries of hypertensive patients undergo characteristic changes in morphology that are closely associated with alterations in vascular function.29 Changes in the small “resistance” arteries are of particular interest, because any alteration in the resistance to flow of these vessels has a substantial effect on arterial pressure.19 The structural and functional consequences of hypertension-induced remodeling have been studied extensively in these vessels. Schiffrin and Deng30 studied the effects of hypertension on the morphology of resistance arteries obtained from subcutaneous gluteal biopsies of 40 normotensive subjects and 45 subjects with untreated essential hypertension. The arteries from the hypertensive patients had a significantly higher media/lumen ratio and a smaller lumen diameter than those from the normotensive subjects. These changes are associated with a number of adverse functional consequences, including amplification of the effects of vasoconstrictors.31 Recent evidence suggests that elevated blood pressure per se may not be responsible for the vascular remodeling that occurs in hypertensive individuals. Schiffrin et al29 compared the effects of treatment with the AT1 receptor blocker losartan and the 1-selective
A SYMPOSIUM: ANGIOTENSIN II IN CARDIVOSACULAR PATHOLOGY
11C
FIGURE 1. Effect of treatment with losartan or atenolol on the media/lumen ratio of resistance arteries from patients with essential hypertension. Individual values and means ⴞ standard error are shown. One year of treatment with losartan resulted in a significant decrease in this ratio, whereas atenolol had no significant effect on this parameter. *p <0.01 versus pretreatment and versus atenolol treatment. (Adapted with permission from Circulation and Lippincott Williams & Wilkins.29)
antagonist atenolol on the characteristics of resistance arteries from patients with essential hypertension. Prior to treatment, the media/lumen ratio of arteries from the hypertensive patients was significantly higher than that of a control group of normotensive subjects. After 1 year of treatment, this ratio had decreased in all 9 patients treated with losartan, and the mean media/lumen ratio of this group was significantly decreased (Figure 1). In contrast, the atenololtreated patients (n ⫽ 10) showed a nonsignificant increase in the media/lumen ratio. Because similar reductions in systolic and diastolic blood pressure were achieved in both groups, the reduced media/ lumen ratio was evidently an effect of AT1 receptor blockade rather than of arterial pressure reduction. Another prominent feature of hypertension-induced vascular remodeling is hypertrophy of vascular smooth muscle cells.20 Angiotensin II has been shown to induce such hypertrophy in vitro,32 and recent work has shown that it does so by activating NADH/ NADPH oxidase.32 In the presence of superoxide dismutase, the superoxide formed during activation of NADH/NADPH oxidase is converted to hydrogen peroxide faster than it can be degraded by catalase.32 Using cells that overexpress catalase, Zafari et al32 showed that this increase in intracellular hydrogen peroxide level is necessary for angiotensin-II–induced hypertrophy to occur. The angiotensin-II–induced increase in peroxide level was inhibited by blockade of the AT1 receptor. Angiotensin II is thus capable of inducing vascular growth by altering the redox state of the cell in a process mediated by the AT1 receptor.32 In addition to studying the effects of losartan and atenolol on the morphology of resistance arteries from hypertensive patients, Schiffrin et al29 compared the effects of these 2 agents on endothelial dysfunction. Before treatment, resistance arteries from the hypertensive patients showed impaired endothelium-depen12C THE AMERICAN JOURNAL OF CARDIOLOGY姞
dent relaxation (ie, reduced dilatory response to acetylcholine) but were no different from control arteries in their response to sodium nitroprusside, an agent that produces endothelium-independent relaxation. The response to acetylcholine was normalized after 1 year of treatment with losartan but remained essentially unchanged after treatment with atenolol (Figure 2). Endothelium-independent relaxation was not affected by either treatment. These studies thus demonstrated that both the morphologic changes and the endothelial dysfunction seen in resistance arteries of hypertensive patients are reversed by AT1 receptor blockade. The fact that these parameters are unaffected by reduction in arterial pressure demonstrates that this is a specific effect of angiotensin II acting at the AT1 receptor. Mechanical properties of the vasculature: In addition to being associated with changes in the structure and function of small arteries, hypertension may also result in changes in the mechanical properties of arterial walls. Although it is generally assumed that hypertension leads to an increase in arterial wall stiffness, this has not been a universal finding, and reports of reduced33 and unchanged34 arterial wall stiffness have also been published. Some of these inconsistencies may be related to the vascular bed under study,35 the parameter used to determine stiffness (eg, compliance and distensibility are to some extent dependent on the geometry of the vessel),20 and the chronicity of the hypertension.20 Park et al20 recently compared the effects of losartan and atenolol on the stiffness of small subcutaneous gluteal arteries in patients with essential hypertension. A geometry-independent measure of arterial wall stiffness was used (slope of the elastic modulus vs stress). After 1 year of treatment, arterial wall stiffness was significantly reduced in the losartan-treated patients but remained unchanged in the atenolol-treated patients (Figure 3). Because the 2 drugs produced sim-
VOL. 87 (8A)
APRIL 19, 2001
FIGURE 2. Effect of treatment with losartan or atenolol on endothelium-dependent (acetylcholine) relaxation of resistance arteries from patients with essential hypertension. Before treatment, both groups of hypertensive patients showed an abnormally reduced dilatory response to acetylcholine. This was normalized by treatment with losartan but not by atenolol. *p <0.05 versus normotensive group. †p <0.05 versus losartan group before treatment and versus atenolol group after treatment. (Adapted with permission from Circulation and Lippincott Williams & Wilkins.29)
FIGURE 3. Effect of treatment with losartan or atenolol on stiffness of resistance arteries from patients with essential hypertension. The slope of the plot of incremental elastic modulus (a geometry-independent measurement of arterial wall stiffness) versus stress was measured before and after treatment with losartan or atenolol. After 1 year of treatment, arteries from the losartan-treated patients showed a significant reduction in wall stiffness, whereas those from atenolol-treated patients did not. *p <0.05 versus “losartan before” measurement. (Reprinted with permission from JRAAS.20)
ilar reductions in blood pressure, this change in stiffness appears to be a direct effect of angiotensin II acting at the AT1 receptor. The reduction in stiffness reported by Park et al20 was associated with a reduction in the media/lumen ratio.29 Angiotensin receptor antagonists are known to inhibit hypertension-induced vascular fibrosis,36 and Park et al20 suggested that the losartan-induced change in mechanical properties may have been mediated by a reduction in the collagen content of the media layer of the vessels. Left ventricular remodeling: An increase in left ventricular mass is a common consequence of hypertension. This condition, often loosely termed left ventric-
ular hypertrophy, is characterized by increases in extracellular matrix (myocardial fibrosis) as well as in myocyte size (true hypertrophy).37 The fibrosis induced by hypertension can be extensive. For example, Querejeta et al38 found that the collagen volume fraction of hearts from individuals with no evidence of cardiovascular disease was 1.95 ⫾ 0.07% (mean ⫾ SEM, range of values 1.39% to 2.15%, n ⫽ 10). In contrast, the collagen volume fraction of 26 hearts from hypertensive patients was 5.23 ⫾ 0.38% (range 2.08% to 9.83%, p ⬍0.001). Because many studies do not distinguish between the contributions of fibrosis and myocyte hypertrophy to hypertension-induced
A SYMPOSIUM: ANGIOTENSIN II IN CARDIVOSACULAR PATHOLOGY
13C
ventricular remodeling, these 2 pathologies will be discussed together. Remodeling of the left ventricle may ultimately lead to systolic dysfunction and cardiac failure.37 Activation of the renin–angiotensin system may contribute to the increase in left ventricular mass seen during hypertension. In vitro, angiotensin II induces hypertrophy of cardiac myocytes and causes cardiac fibroblasts to accumulate collagen.1,10,12 In vivo, angiotensin II induces myocardial collagen deposition, myocyte hypertrophy, and increased left ventricular mass.1,10,12 These effects are all mediated by the AT1 receptor.1,10,12 Both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been shown to prevent and reverse hypertension-induced increases in left ventricular mass and collagen deposition in a variety of murine models of hypertension.1,10,12 For example, Ikeda et al39 treated stroke-prone spontaneously hypertensive rats with the AT1 receptor antagonist candesartan, the angiotensin-converting enzyme inhibitor captopril, or hydralazine, an antihypertensive agent that does not affect the renin–angiotensin system. Treatment was started at 12 weeks of age, by which time the rats had already developed substantial left ventricular hypertrophy. At 24 weeks of age, untreated spontaneously hypertensive rats had decreased coronary reserve, left ventricular hypertrophy, increased myocyte size, and increased interstitial collagen volume fraction. In contrast, in spontaneously hypertensive rats treated from 12 to 24 weeks of age with captopril or candesartan, measurements of left ventricular weight, myocyte size, and interstitial collagen volume fraction were all similar to those of normal control animals. Treatment with hydralazine decreased the collagen volume fraction, but this was the only measure of cardiac remodeling on which it had a positive effect. Similar results were obtained by Yamazaki and Yazaki,40 who treated spontaneously hypertensive rats with candesartan or hydralazine. Left ventricular weight, left ventricular wall thickness, transverse myocyte diameter, and the amount of interstitial fibrosis were all lower in the candesartan-treated rats than in untreated controls. Treatment with hydralazine had a small effect on the increase in left ventricular wall thickness but no significant effect on the other parameters. The results of these 2 studies39,40 suggest that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers prevent hypertension-induced cardiac remodeling by interacting with the AT1 receptor and that this effect is not mediated by changes in arterial pressure. In humans, reducing the activity of the renin– angiotensin system is a more effective method of reversing hypertension-induced left ventricular remodeling than diuresis, -receptor blockade, or calcium channel blockade. In a meta-analysis of 109 studies, Dahlo¨f et al41 calculated the reduction in left ventricular mass achieved by angiotensin-converting enzyme inhibitors, calcium antagonists, -blockers, and thiazide diuretics. When the data were examined 14C THE AMERICAN JOURNAL OF CARDIOLOGY姞
using the same formula for all studies, the reductions in mass achieved by these 4 drug classes were 16%, 10%, 9%, and 8%, respectively. Overall, there was a significant correlation between the reductions in left ventricular mass and mean arterial pressure, but this relation still explained only 29% of the reduction in mass. When the reduction in left ventricular mass was expressed as a function of the reduction in mean arterial pressure, angiotensin-converting enzyme inhibitors were superior to the other 3 drug classes with an average reduction in mass of 2.3 g/mm Hg reduction in pressure (Figure 4).41 Calcium antagonists achieved an average reduction of 1.4 g/mm Hg; thiazide diuretics, 1.1 g/mm Hg; and -blockers, 0.9 g/mm Hg. A recent meta-analysis that used more stringent inclusion criteria and a smaller number of clinical trials (n ⫽ 39)42 confirmed the superiority of angiotensin-converting enzyme inhibitors over other antihypertensive medications for reducing left ventricular mass. Data from human clinical trials also suggest that angiotensin II, acting through the AT1 receptor, is involved in the production of left ventricular hypertrophy. For example, losartan has been shown to reduce left ventricular mass in hypertensive patients43,44 and is substantially more effective than the thiazide diuretic hydrochlorothiazide in this regard.43
ANGIOTENSIN-II–INDUCED CARDIOVASCULAR FIBROSIS MAY BE MEDIATED BY TGF-1
Transforming growth factor-1 (TGF-1) is known to be important in the regulation of extracellular matrix production, and overproduction of this agent is associated with fibrogenesis.45 There is growing evidence that the fibrosis induced by angiotensin II may be mediated by this cytokine.12,46 For example, Kagami et al47 showed that rat mesangial cells respond to treatment with angiotensin II by increasing the synthesis of TGF-1 mRNA, TGF-1 protein, and various components of the extracellular matrix, including type I collagen. Coincubation of the cells with angiotensin II and neutralizing antibody to TGF-1 blocked the angiotensin-II–induced synthesis of extracellular matrix components, suggesting that the fibrotic response of mesangial cells to angiotensin II is dependent on TGF-1. The association between angiotensin II, TGF-1, and fibrosis is also apparent in vivo. In various murine models of vascular disease, including hypertension, the reduction in cardiovascular hypertrophy and extracellular matrix production that results from administration of an angiotensin receptor blocker is accompanied by suppressed production of TGF-1 and collagen types I, III, and IV.1 This suggests that the association between angiotensin II, TGF-1, and fibrosis is mediated by the AT1 receptor. There is growing evidence that various forms of nephropathy and hypertension-induced pathology in humans may be jointly mediated by TGF-1 and angiotensin II. Suthanthiran et al48 showed that serum TGF-1 levels are significantly higher in hypertensive
VOL. 87 (8A)
APRIL 19, 2001
FIGURE 4. Results of a meta-analysis of the effects of 4 antihypertensive treatments on calculated left ventricular mass, normalized to the reduction in mean arterial pressure. Angiotensinconverting enzyme inhibitors achieved a greater reduction in left ventricular mass per mm Hg reduction in mean arterial pressure than did -blockers, thiazide diuretics, or calcium antagonists. ACE ⴝ angiotensin-converting enzyme; CCB ⴝ calcium channel blocker; LV ⴝ left ventricle; MAP ⴝ mean arterial pressure. (Data from Am J Hypertens.41)
individuals than in those with normal blood pressure. In addition, within both normotensive and hypertensive populations, black individuals had higher TGF-1 levels than white individuals did.48 This ethnic difference is of interest because blacks not only have higher rates of hypertension than whites do49 but also have a higher incidence of conditions commonly associated with hypertension such as left ventricular hypertrophy,50 ischemic stroke,51 and end-stage renal disease.52 TGF-1 levels have been shown to correlate with blood pressure in patients with end-stage renal disease,53 and blacks with this disease have higher TGF-1 levels than whites do.54 Recent work in human patients with various forms of nephropathy has shown that the beneficial clinical effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be mediated by reductions in TGF-1 expression. For example, Nishimura et al55 studied the effects of treatment with angiotensin-converting enzyme inhibitors on the level of TGF-1 mRNA in renal biopsies from patients with IgA nephropathy. Although patients treated with angiotensin-converting enzyme inhibitors had a worse initial prognosis (based on factors such as disease duration and degree of proteinuria), the level of TGF-1 mRNA in these patients was only 60% of the level in untreated patients at the end of the study. Sharma et al56 measured serum levels of TGF-1 in patients with diabetic nephropathy before and after 6 months of treatment with placebo or with the angiotensin-converting enzyme inhibitor captopril. Over this 6-month period, TGF-1 levels increased by 11% in the placebo group (p ⫽ 0.003) and decreased by 14% in the captopril group (p ⫽ 0.01). In both groups of patients, the percent change in TGF-1 level during this 6-month period showed a significant inverse correlation with the percent change in glomerular filtration rate that occurred in the ensuing 2 years. This
correlation was strongest (r ⫽ ⫺0.73, p ⫽ 0.0001) in captopril-treated patients with renal insufficiency at baseline (glomerular filtration rate ⬍75 mL/min). Changes in serum creatinine, mean arterial pressure, proteinuria, and glycosylated hemoglobin were not predictive of the change in glomerular filtration rate. Sharma et al56 did not determine the mechanism by which captopril elicited these beneficial changes in TGF-1 level and renal function. However, work by Campistol et al57 strongly suggests that reduced stimulation of the AT1 receptor is involved. These authors measured plasma TGF-1 levels in patients with chronic allograft nephropathy before and after treatment with the angiotensin receptor blocker losartan. TGF-1 has been implicated in the pathogenesis of chronic renal allograft dysfunction.58 Before treatment, this cytokine was present at higher levels in the patients with nephropathy than in a control group of transplant patients with normal renal function. Losartan significantly decreased TGF-1 levels, and the decrease in TGF-1 was correlated with blockade of the angiotensin II receptor. This finding suggests that binding of the AT1 receptor initiates TGF-1 synthesis. One reason that the roles of angiotensin II and TGF-1 have been studied so extensively in models of nephropathy is that the kidney is particularly susceptible to TGF-1–induced fibrosis.45 However, there is also evidence that TGF-1 plays a role in the cardiovascular remodeling induced by hypertension. Villarreal and Dillmann59 showed that TGF-1 mRNA increased within 12 hours of the onset of experimental pressure overload and that this increase preceded increased expression of extracellular matrix proteins and cardiac hypertrophy. Everett et al60 studied the effect of AT1 receptor blockade on the cardiac hypertrophy induced by coarctation of the aorta. In rats that received no pharmacologic treatment after coarctation,
A SYMPOSIUM: ANGIOTENSIN II IN CARDIVOSACULAR PATHOLOGY
15C
the development of cardiac hypertrophy (defined as an increase in the heart weight to body weight ratio) was associated with a 2-fold increase in TGF-1 mRNA levels.60 In contrast, animals treated with losartan after coarctation demonstrated neither cardiac hypertrophy nor elevated TGF-1 levels. Further evidence for a link between TGF-1, angiotensin II, and cardiac fibrosis comes from work carried out using a rat model of nitric oxide synthase inhibition. Tomita et al61 showed that the cardiac fibrosis that is induced in this model is preceded by increases in cardiac TGF-1 and extracellular matrix protein mRNA levels. TGF-1 immunoreactivity was increased in areas of fibrosis.61 Administration of an angiotensin II type 1 receptor antagonist, but not hydralazine, prevented both the cardiac fibrosis and the increased TGF-1 and extracellular matrix protein expression. Tomita et al61 also demonstrated that administration of a neutralizing antibody against TGF-1 did not prevent the increase in TGF-1 mRNA levels but did prevent the increase in extracellular matrix protein mRNA levels. Thus, in this model, angiotensin-II–induced TGF-1 production plays a major role in the development of cardiac fibrosis.
TGF-1 MAY REPRESENT A COMMON PATHWAY FOR ANGIOTENSIN-II–INDUCED AND STRAIN-INDUCED CARDIOVASCULAR FIBROSIS In both mesangial and vascular smooth muscle cells, mechanical strain increases TGF-1 mRNA and protein synthesis, and induces elaboration of extracellular matrix.62,63 In both of these cell types, the straininduced increase in extracellular matrix protein synthesis is inhibited by the presence of neutralizing or blocking antibodies to TGF-1.62,63 Because the strain to which cardiovascular tissues are exposed may be increased by increased arterial pressure,22 these data imply that the increased extracellular matrix synthesis and cardiovascular fibrosis that occur in response to hypertension may be mediated, at least in part, by strain-induced increases in TGF-1 levels. As discussed above, TGF-1 expression can also be induced by angiotensin II acting at the AT1 receptor. Strain-induced and angiotensin-II–induced cardiovascular fibrosis may therefore proceed by the same mechanism. In hypertensive patients in whom both arterial strain and angiotensin II levels are elevated, these pathways may constitute a dual mechanism whereby cardiovascular fibrosis is accelerated.
CONCLUSION Angiotensin II is widely involved in the pathogenesis of hypertension-induced changes in cardiovascular morphology and function. In addition to causing elevated arterial pressure per se, angiotensin II is also involved in detrimental changes in vascular morphology, endothelial function, and vessel wall stiffness, and induces left ventricular hypertrophy and myocar16C THE AMERICAN JOURNAL OF CARDIOLOGY姞
dial fibrosis. These actions are mediated by the AT1 receptor. The finding that mechanical strain induces upregulation of the AT1 receptor suggests that the pathologic changes in the vasculature associated with hypertension may result from sensitization of vascular smooth muscle cells to angiotensin II. Angiotensin II receptor blockade may thus allow hypertensive individuals to avoid many of the consequences of the disease, including the systolic dysfunction that results from left ventricular remodeling, and the end-stage renal failure that afflicts so many hypertensive patients.
1. Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated
cardiovascular and renal diseases. Pharmacol Rev 2000;52:11–34. 2. Seravalle G, Cattaneo BM, Giannattasio C, Perondi R, Saino A, Grassi G,
Mancia G. RAA system and cardiovascular control in normal subjects, hypertensives and patients with congestive heart failure. J Hum Hypertens 1993; 7(suppl 2):S13–18. 3. Alderman MH, Madhavan S, Ooi WL, Cohen H, Sealey JE, Laragh JH. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med 1991;324:1098 –1104. 4. Warnholtz A, Nickenig G, Schulz E, Macharzina R, Bra¨sen JH, Skatchkov M, Heitzer T, Stasch JP, Griendling KK, Harrison DG, et al. Increased NADHoxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system. Circulation 1999;99: 2027–2033. 5. Pratt RE. Angiotensin II and the control of cardiovascular structure. J Am Soc Nephrol 1999;10:S120 –S128. 6. Schieffer B, Schieffer E, Hilfiker-Kleiner D, Hilfiker A, Kovanen PT, Kaartinen M, Nussberger J, Harringer W, Drexler H. Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability. Circulation 2000;101:1372–1378. 7. Remuzzi A, Perico N, Sangalli F, Vendramin G, Moriggi M, Ruggenenti P, Remuzzi G. ACE inhibition and ANG II receptor blockade improve glomerular size-selectivity in IgA nephropathy. Am J Physiol 1999;276:F457–F466. 8. Munzenmaier DH, Greene AS. Opposing actions of angiotensin II on microvascular growth and arterial blood pressure. Hypertension 1996;27:760 –765. 9. Williams B. A potential role for angiotensin II-induced vascular endothelial growth factor expression in the pathogenesis of diabetic nephropathy? Miner Electrolyte Metab 1998;24:400 – 405. 10. Lijnen P, Petrov V. Antagonism of the renin-angiotensin system, hypertrophy and gene expression in cardiac myocytes. Methods Find Exp Clin Pharmacol 1999;21:363–374. 11. Rajagopalan S, Kurz S, Mu¨nzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Invest 1996;97:1916 –1923. 12. Lijnen P, Petrov V. Antagonism of the renin-angiotensin-aldosterone system and collagen metabolism in cardiac fibroblasts. Methods Find Exp Clin Pharmacol 1999;21:215–227. 13. Carey RM, Wang Z-Q, Siragy HM. Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function. Hypertension 2000;35: 155–163. 14. Gallinat S, Busche S, Raizada MK, Sumners C. The angiotensin II type 2 receptor: an enigma with multiple variations. Am J Physiol Endocrinol Metab 2000;278:E357–E374. 15. Tsutsumi Y, Matsubara H, Masaki H, Kurihara H, Murasawa S, Takai S, Miyazaki M, Nozawa Y, Ozono R, Nakagawa K, et al. Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation. J Clin Invest 1999;104:925–935. 16. Morrissey JJ, Klahr S. Effect of AT2 receptor blockade on the pathogenesis of renal fibrosis. Am J Physiol 1999;276:F39 –F45. 17. Campbell DJ, Kladis A, Valentijn AJ. Effects of losartan on angiotensin and bradykinin peptides and angiotensin-converting enzyme. J Cardiovasc Pharmacol 1995;26:233–240. 18. Koren MJ, Devereuz RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991;114:345–352. 19. Schiffrin EL. Reactivity of small blood vessels in hypertension: relation with structural changes. State of the art lecture. Hypertension 1992;19(suppl II):II-1– II-9. 20. Park JB, Intengan HD, Schiffrin EL. Reduction of resistance artery stiffness by treatment with the AT1-receptor antagonist losartan in essential hypertension. JRAAS 2000;1:40 – 45. 21. Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. Abnormal endotheliumdependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990;323:22–27.
VOL. 87 (8A)
APRIL 19, 2001
22. Safar ME, Peronneau PA, Levenson JA, Toto-Moukouo JA, Simon AC. Pulsed Doppler: diameter, blood flow velocity, and volumic flow of the brachial artery in sustained essential hypertension. Circulation 1981;63:393– 400. 23. Williams B. Mechanical influences on vascular smooth muscle cell function. J Hypertens 1998;16:1921–1929. 24. Stanley AG, Knight AL, Williams B. Mechanical strain sensitizes human vascular smooth muscle cells to angiotensin II [abstract]. Am J Hypertens 2000; 13:12A. 25. Liao D-F, Duff JL, Daum G, Pelech SL, Berk BC. Angiotensin II stimulates MAP kinase kinase kinase activity in vascular smooth muscle cells: role of Raf. Circ Res 1996;79:1007–1014. 26. Li D, Saldeen T, Romeo F, Mehta JL. Oxidized LDL upregulates angiotensin II type 1 receptor expression in cultured human coronary artery endothelial cells: the potential role of transcription factor NF-B. Circulation 2000;102:1970 – 1976. 27. Li DY, Zhang YC, Philips MI, Sawamura T, Mehta JL. Upregulation of endothelial receptor for oxidized low-density lipoprotein (LOX-1) in cultured human coronary artery endothelial cells by angiotensin II type 1 receptor activation. Circ Res 1999;84:1043–1049. 28. Robert V, Heymes C, Silvestre J-S, Sabri A, Swynghedauw B, Delcayre C. Angiotensin AT1 receptor subtype as a cardiac target of aldosterone: role in aldosterone-salt-induced fibrosis. Hypertension 1999;33:981–986. 29. Schiffrin EL, Park JB, Intengan HD, Touyz RM. Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan. Circulation 2000;101:1653–1659. 30. Schiffrin EL, Deng LY. Relationship between small-artery structure and systolic, diastolic and pulse pressure in essential hypertension. J Hypertens 1999;17:381–387. 31. Deng LY, Schiffrin EL. Effects of endothelin-1 and vasopressin on resistance arteries of spontaneously hypertensive rats. Am J Hypertens 1992;5:817– 822. 32. Zafari AM, Ushio-Fukai M, Akers M, Yin Q, Shah A, Harrison DG, Taylor WR, Griendling KK. Role of NADH/NADPH oxidase-derived H2O2 in angiotensin II-induced vascular hypertrophy. Hypertension 1998;32:488 – 495. 33. Intengan HD, Deng LY, Li JS, Schiffrin EL. Mechanics and composition of human subcutaneous resistance arteries in essential hypertension. Hypertension 1999;33:569 –574. 34. Thybo NK, Mulvany MJ, Jastrup B, Nielsen H, Aalkjaer C. Some pharmacological and elastic characteristics of isolated subcutaneous small arteries from patients with essential hypertension. J Hypertens 1996;14:993–998. 35. Safar ME, London GM. Arterial stiffness in hypertensive subjects with or without end-stage renal disease. Kidney Blood Press Res 1997;20:82– 89. 36. Kim S, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K, Inada Y, Ishimura Y, Chatani F, Iwao H. Angiotensin II type 1 receptor antagonist inhibits the gene expression of transforming growth factor-1 and extracellular matrix in cardiac and vascular tissues of hypertensive rats. J Pharmacol Exp Ther 1995; 273:509 –515. 37. Brilla CG, Maisch B. Regulation of the structural remodelling of the myocardium: from hypertrophy to heart failure. Eur Heart J 1994:15(suppl D):45–52. 38. Querejeta R, Varo N, Lo´pez B, Larman M, Artin˜ano E, Etayo JC, Martı´nez Ubago JLM, Gutierrez-Stampa M, Emparanza JI, Gil MJ, et al. Serum carboxyterminal propeptide of procollagen type 1 is a marker of myocardial fibrosis in hypertensive heart disease. Circulation 2000;101:1729 –1735. 39. Ikeda Y, Nakamura T, Takano H, Kimura H, Obata J-E, Takeda S, Hata A, Shido K, Mochizuki S, Yoshida Y. Angiotensin II-induced cardiomyocyte hypertrophy and cardiac fibrosis in stroke-prone spontaneously hypertensive rats. J Lab Clin Med 2000;135:353–359. 40. Yamazaki T, Yazaki Y. Role of tissue angiotensin II in myocardial remodeling induced by mechanical stress. J Hum Hypertens 1999;13(suppl 1):S43– 47. 41. Dahlo¨f B, Pennert K, Hansson L. Reversal of left ventricular hypertrophy in hypertensive patients: a metaanalysis of 109 treatment studies. Am J Hypertens 1992;5:95–110. 42. Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension: a meta-analysis of randomized double-blind studies. JAMA 1996;275:1507–1513. 43. Tedesco MA, Ratti G, Aquino D, Limongelli G, Di Salvo G, Mennella S, Galzerano D, Iarussi D, Iacono A. Effects of losartan on hypertension and left ventricular mass: a long-term study. J Hum Hypertens 1998;12:505–510.
44. Avanza AC Jr, El Aouar LM, Mill JG. Reduction in left ventricular hyper-
trophy in hypertensive patients treated with enalapril, losartan or the combination of enalapril and losartan [in Portuguese]. Arq Bras Cardiol 2000;74:111–117. 45. Border WA, Noble NA. Interactions of transforming growth factor- and angiotensin II in renal fibrosis. Hypertension 1998;31:181–188. 46. Weber KT, Swamynathan SK, Guntaka RV, Sun Y. Angiotensin II and extracellular matrix homeostasis. Int J Biochem Cell Biol 1999;31:395– 403. 47. Kagami S, Border WA, Miller DE, Noble NA. Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor- expression in rat glomerular mesangial cells. J Clin Invest 1994;93: 2431–2437. 48. Suthanthiran M, Li B, Song JO, Ding R, Sharma VK, Schwartz JE, August P. Transforming growth factor-1 hyperexpression in African-American hypertensives: a novel mediator of hypertension and/or target organ damage. Proc Natl Acad Sci U S A 2000;97:3479 –3484. 49. Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, Horan MJ, Labarthe D. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension 1995;25:305–313. 50. Taylor JO, Borhani NO, Entwisle G, Farber M, Hawkins CM, on behalf of the HDFP Cooperative Group. Summary of the baseline characteristics of the hypertensive participants. Hypertension 1983;5(suppl IV):IV-44 –IV-50. 51. Rosamond WD, Folsom AR, Chambless LE, Wang C-H, McGovern PG, Howard G, Copper LS, Shahar E. Stroke incidence and survival among middleaged adults: 9-year follow-up of the Atherosclerosis Risk in Communities (ARIC) cohort. Stroke 1999;30:736 –743. 52. Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, Stamler J. End-stage renal disease in African-American and white men: 16-year MRFIT findings. JAMA 1997;277:1293–1298. 53. Li B, Khanna A, Sharma V, Singh T, Suthanthiran M, August P. TGF-1 DNA polymorphisms, protein levels, and blood pressure. Hypertension 1999b; 33:271–275. 54. Suthanthiran M, Khanna A, Cukran D, Adhikarla R, Sharma VK, Singh T, August P. Tranforming growth factor-1 hyperexpression in African American end-stage renal disease patients. Kidney Int 1998;53:639 – 644. 55. Nishimura M, Okamura M, Konishi Y, Inoue K, Young CK, Yoshioka T, Negoro N, Inoue T, Kanayama Y. Effect of treatment with ACE inhibitor (ACEI) on TGF-beta gene expressions in renal biopsy from patients with IgA nephropathy [abstract]. J Am Soc Nephrol 1995;6:397. 56. Sharma K, Eltayeb BO, McGowan TA, Dunn SR, Alzahabi B, Rohde R, Ziyadeh FN, Lewis EJ. Captopril-induced reduction of serum levels of transforming growth factor-1 correlates with long-term renoprotection in insulindependent diabetic patients. Am J Kidney Dis 1999;34:818 – 823. 57. Campistol JM, Inigo P, Jimenez W, Lario S, Clesca PH, Oppenheimer F, Rivera F. Losartan decreases plasma levels of TGF-1 in transplant patients with chronic allograft nephropathy. Kidney Int 1999;56:714 –719. 58. Horvath LZ, Friess H, Schilling M, Borisch B, Deflorin J, Gold LI, Korc M, Buchler MW. Altered expression of transforming growth factor-s in chronic renal rejection. Kidney Int 1996;50:489 – 498. 59. Villarreal FJ, Dillmann WH. Cardiac hypertrophy-induced changes in mRNA levels for TGF-1, fibronectin, and collagen. Am J Physiol 1992;262:H1861– H1866. 60. Everett AD, Tufro-McReddie A, Fisher A, Gomez RA. Angiotensin receptor regulates cardiac hypertrophy and transforming growth factor-1 expression. Hypertension 1994;23:587–592. 61. Tomita H, Egashira K, Ohara Y, Takemoto M, Koyanagi M, Katoh M, Yamamoto H, Tamaki K, Shimokawa H, Takeshita A. Early induction of transforming growth factor- via angiotensin II type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats. Hypertension 1998;32:273–279. 62. Hirakata M, Kaname S, Chung U-G, Joki N, Hori Y, Noda M, Takuwa Y, Okazaki T, Fujita T, Katoh T, Kurokawa K. Tyrosine kinase dependent expression of TGF- induced by stretch in mesangial cells. Kidney Int 1997;51:1028 – 1036. 63. O’Callaghan CJ, Williams B. Mechanical strain-induced extracellular matrix production by human vascular smooth muscle cells: role of TGF-1. Hypertension 2000;36:319 –324.
A SYMPOSIUM: ANGIOTENSIN II IN CARDIVOSACULAR PATHOLOGY
17C