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remodeling following infarction
Journal of Molecular and Cellular Cardiology 48 (2010) 483–489
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Journal of Molecular and Cellular Cardiology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y j m c c
Review article
Intracardiac renin–angiotensin system and myocardial repair/remodeling following infarction Yao Sun ⁎ Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, 956 Court Ave. Rm B324A, Memphis, TN 38163, USA
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Article history: Received 4 May 2009 Received in revised form 29 July 2009 Accepted 4 August 2009 Available online 12 August 2009 Keywords: Myocardial infarction Cardiac repair Cardiac remodeling Cardiac RAS Ventricular dysfunction
a b s t r a c t The circulating renin-angiotensin system (RAS) is a classic endocrine system that regulates cardiovascular homeostasis during physiologic and pathologic states. Accumulated evidence has shown the presence of components of RAS in various tissues, which are upregulated in certain pathological conditions. Locally produced angiotensin (Ang)II may play an important role in tissue repair/remodeling in autocrine and/or paracrine manners. Following acute myocardial infarction (MI), cardiac repair occurs in the infarcted myocardium and structural remodeling is developed in noninfarcted myocardium, which are accompanied by activated cardiac RAS. In this review, the current understanding of independent activation of cardiac RAS and its regulation in the pathogenesis of myocardial repair/remodeling after MI is discussed. © 2009 Elsevier Ltd. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . Cardiac repair/remodeling following infarction . . . . . . . 2.1. Infarcted myocardium . . . . . . . . . . . . . . . . 2.2. Noninfarcted myocardium . . . . . . . . . . . . . . 3. Activation of cardiac angiotensin system in the infarcted heart 4. Regulation of AngII on cardiac repair/remodeling postMI . . . 4.1. Infarcted myocardium . . . . . . . . . . . . . . . . 4.2. Noninfarcted myocardium . . . . . . . . . . . . . . 5. Summary and future directions . . . . . . . . . . . . . . . Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction The critical role of the circulating RAS in the regulation of arterial pressure and sodium homeostasis has been recognized for many years. AngII is the most powerful biologically active product of the RAS. AngII directly constricts vascular smooth muscle cells, enhances myocardial contractility, stimulates aldosterone production, stimulates release of catecholamines from the adrenal medulla and sympathetic nerve endings, increases sympathetic nervous system activity, and stimulates thirst and salt appetite. AngII also regulates sodium transport by epithelial cells in the intestine and kidney.
⁎ Tel./fax: +1 901 448 4921. E-mail address: [email protected]. 0022-2828/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.yjmcc.2009.08.002
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RAS is a coordinated hormonal cascade. Renin acts on the circulating precursor angiotensinogen to form AngI. AngI has no biological activity and is converted to AngII by endothelial angiotensin-converting enzyme (ACE). The actions of AngII are mediated by specific membrane-bound AngII type-1 (AT1) and type-2 (AT2) receptors with the majority of cardiovascular actions of AngII are mediated by the AT1 receptors. AT2 receptors induce a counterregulatory vasodilatation that is largely mediated by bradykinin and nitric oxide. AngII has a very short half-life and is quickly degraded to active AngIII and Ang(1–7) and inactive fragments. AngIII has actions similar to those of AngII. Ang(1–7), via Mas receptors, exerts the hypotensive action through the release of bradykinin, prostaglandins, and endothelial nitric oxide [1]. Thus, Ang(1–7) acts as an endogenous inhibitor of AngII. ACE2 is the newest member of the RAS [1]. ACE2 is primarily expressed in endothelial cells in the heart and kidney. It
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hydrolyzes AngII to Ang(1–7) and its enzymatic activity is not affected by ACE inhibitors. There has also been a growing appreciation of the organ-specific roles exerted by AngII acting as an autocrine/paracrine factor. Local AngII production is activated in various pathological states, such as atherosclerosis [2], various injured tissues [3], hypertensive and diabetic kidney [4,5], MI [6,7], etc. AngII has been demonstrated to stimulate inflammation, cell growth, apoptosis, fibrogenesis, and differentiation, regulates the gene expression of bioactive substances, and activates multiple intracellular signaling pathways, all of which might contribute to tissue repair/remodeling [8,9]. Following MI, structural changes appear in both the infarcted and noninfarcted myocardium. Cardiac repair occurs in the infarcted myocardium, which is associated with an inflammatory reaction, angiogenesis and scar formation. Structural remodeling in the noninfarcted myocardium includes hypertrophy and interstitial fibrosis [10–12]. Fibrous tissue that forms at the site of cardiomyocyte loss preserves structural integrity and is integral to the heart's recovery, whereas structural remodeling of viable myocardium impairs tissue behavior. Substances involved in cardiac repair/remodeling are of considerable interest and an important clinical issue. Multiple factors may, in fact, contribute to left ventricular remodeling at different stages
postMI. There is growing recognition and experimental evidence that cardiac RAS is activated following MI and locally produced AngII plays a central role in the pathogenesis of myocardial repair/remodeling after MI. This review will in particular address the regulation of locally produced AngII in promoting cardiac repair/remodeling following MI. 2. Cardiac repair/remodeling following infarction 2.1. Infarcted myocardium A highly regulated process of cardiac repair follows the necrotic loss of cardiomyocytes after MI. It begins with the activation of matrix metalloproteinases (MMPs), which degrade the existing extracellular matrix and coronary vasculature in the infarcted myocardium [13,14]. This proteolytic activity declines by the end of week 1 postMI [13,14]. Circulating leukocytes infiltrate into the infarct site soon after MI, while monocyte-derived macrophages are the major population of inflammatory cells in the infarcted myocardium (Fig. 1). The leukocytes home to the site of MI drawn by adhesion molecules and chemokines expressed by the endothelial cells of the coronary vasculature that borders on the infarct site [15,16]. Their migration into the infarct site is facilitated by MMP proteolytic activity.
Fig. 1. Cardiac fibrosis and cells responsible for cardiac repair postMI: Following MI, abundant ED-1+ macrophages appear in the infarcted myocardium at week 1 (panel A, brown), while the population of neutrophils and lymphocytes is low (not shown). Interstitial α-SMA+ myoFb are not present in the normal myocardium (panel B, arrows: blood vessels). Following MI, myoFb (brown) are accumulated in the infarcted myocardium at week 1 and located primarily around necrotic tissue (Nec) (panel C). Normal myocardium contains a small amount of collagen (red, picrosirius red staining) in the interstitial space (panel D). Following MI, scar is formed in the infarcted myocardium (panel E) and interstitial fibrosis (panel F) is developed in the noninfarcted myocardium at 4 weeks postMI.
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Inflammatory response in the infarcted myocardium involves the coordinated activation of a series of cytokine and adhesion molecule genes. A critical element in the regulation of these genes involves nuclear factor-kappa B (NF-κB), which triggers gene expression of proinflammatory cytokines, initiating an inflammatory response [17]. In rodent models of MI, NF-κB is activated primarily in macrophages of infarcted myocardium [18], which is accompanied with upregulated TNF-α expression and inflammatory response, including inflammatory protein synthesis, macrophage phagocytosis, cell growth, differentiation and apoptosis [18,19]. Macrophages also release angiogenic promoters, such as vascular endothelial growth factor (VEGF) [20,21], triggering angiogenesis in the infarcted myocardium. The inflammatory response and angiogenesis peak at weeks 1 and 2 postMI and then taper off. Inflammatory cells disappear from the infarct site within 2–3 weeks after MI, a consequence of their programmed cell death, while cardiac angiogenesis becomes quiescent when the healing is completed. The inflammatory response and angiogenesis are the vitally necessary mechanisms of healing of injured myocardium. These processes remove damaged/necrotic tissue, establish a vascular supply to support repair, and stimulate scar formation. However, an exuberant inflammatory response has a direct deleterious effect on myocyte, leading further myocardial damage in the border zones and thus expanding infarct size in the animal experiments. However, in human trials, none of the applied anti-inflammatory medications reached a convincing clinical impact. These observations emphasize the need for better understanding of the cellular and molecular events associated with the inflammatory response in order to achieve effective suppression of injurious processes without interfering with healing and cardiac repair. The fibrogenic component, which substitutes for lost parenchymal cells, follows the initial phase of collagen degradation. It begins with
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the activation of transforming growth factor (TGF)-β1 [22], the key mediator of fibrogenesis, released primarily by inflammatory cells. Increased synthesis of fibrillar type III and type I collagens is preceded by an increased expression of their mRNA transcripts [12]. Collagen fibers are morphologically evident at week 1 postMI, while an organized assembly of these fibers in the form of scar tissue becomes evident at week 2. This assembly continues to accumulate in the following weeks (Fig. 1). Cells responsible for fibrous tissue formation at the site of MI are phenotypically transformed fibroblasts, myofibroblasts (MyoFb) (Fig. 1) [23]. MyoFb appear at the infarct site soon after the arrival of inflammatory cells [6]. Cells that account for the appearance of myoFb have been demonstrated to include interstitial fibroblasts, pericytes, macrophages, or circulating bone marrow-derived progenitor cells that transdifferentiate at the infarct site. Specific factors that facilitate this differentiation process have been identified. It is presumed that TGF-β1, elaborated by macrophages, governs the appearance of the myoFb phenotype [24]. After appearance, MyoFb rapidly proliferate and are responsible for formation of the scar via their expression of type I and III fibrillar collagens at both mRNA and protein levels [12,22]. The number of MyoFb is gradually declined from the scar tissue through apoptosis after cardiac repair is completed. 2.2. Noninfarcted myocardium Interstitial fibrosis is developed in the noninfarcted myocardium, particularly in the heart with large MI (Fig. 1). It is observed in the absence of cell loss. TGF-β1 level and collagen synthesis is enhanced in the noninfarcted myocardium within several weeks postMI [12,22]. Fibrous tissue accumulation is observed in the noninfarcted myocardium in the rat heart with extensive MI [12]. Perivascular fibrosis of intramyocardial coronary arteries is also seen at the site. Cells
Fig. 2. Autoradiographic ACE and AngII receptor binding: In the normal heart, a low density of ACE binding is present in the left and right ventricle (LV, RV), while blood vessels express higher levels of ACE (bright spots) (panel A). Following MI, ACE binding is largely increased in the infarcted myocardium (MI) at week 1 (panel B) and in following weeks (not shown). ACE is also increased in the noninfarcted myocardium, but to a much lesser extent compared to the infarcted myocardium (panel B). Normal heart contains low level of AngII receptors (panel C). AngII receptor binding is markedly increased, particularly in the infarcted myocardium at week 1 (panel D) and remains elevated over the course of 4 weeks (not shown). S: septum.
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contributing to fibrosis in the noninfarcted myocardium are primarily interstitial fibroblasts. MyoFb are not observed in the noninfarcted myocardium and are not responsible for the development of interstitial fibrosis. Interstitial fibrosis can enhance myocardial stiffness and contributes to ventricular dysfunction. Mechanisms responsible for the appearance of interstitial fibrosis in noninfarcted myocardium are, however, not fully understood. It may involve either a direct effect of stretch and/or a diffusion of fibrogenic mediators that originate in the infarcted myocardium through the interstitial space. 3. Activation of cardiac angiotensin system in the infarcted heart Renin expression (mRNA and protein) is undetectable in the normal rat myocardium, indicating that renin is not produced in the normal heart [7,25]. Following experimental MI, renin expression is significantly increased in the infarcted rat myocardium and cells expressing renin are primarily macrophages and myofibroblasts, demonstrating that renin is synthesized in the infarcted heart [7,25]. Other studies, however, suggest that cardiac renin and AngI can be taken up from the circulation. Low ACE levels are present throughout the myocardium of the right and left atria and ventricles of the normal adult rat heart, as is also the case for AngII receptors. ACE and AT1 receptor expressions are significantly increased at the infarcted myocardium (Fig. 2), coincident with inflammatory response, angiogenesis and the accumulation of fibrillar collagen [6,26]. Moreover, elevated AngII concentration is found at the infarct site [27]. In the infarcted myocardium, ACE is expressed by endothelial cells of the neovasculature, macrophages and myoFb [6,28]; and AT1 receptors primarily by macrophages, myoFb and vascular smooth muscle cells [29]. The expression of ACE and AT1 receptors in macrophages and myoFb in the infarcted myocardium suggest that locally generated AngII plays a role in inflammatory and fibrogenic reactions in an autocrine manner, which is mediated by AT1 receptors. ACE level is also found significantly increased in the noninfarcted myocardium, but to a much lesser extent compared to the infarcted myocardium [6]. The activation of cardiac RAS following MI is, however, not often accompanied by elevated circulating RAS in the early stage of MI [30], suggesting that RAS activation in the repairing myocardium is independent of circulating RAS. Cardiac dysfunction with activated circulating RAS is mostly developed in the later stage of MI (N4 weeks). Nonischemic models of cardiac repair have also been examined relative to high ACE expression, including AngII infusion via an implanted mini-pump [31]; administration of isoproterenol, a synthetic catecholamine [3]; and chronic (N3 weeks) administration of aldosterone by mini-pump in uninephrectomized rats on a high salt diet [32]. At each site of nonischemic cardiac repair, and irrespective of its etiologic basis, the temporal and spatial appearance of high levels of ACE expression is coincident with inflammatory response and fibrous tissue formation that resembles reparative responses observed with ischemic necrosis following MI. Thus, regardless of the etiologic basis of cardiac injury, ACE appears at sites of cardiac repair and contributes to local AngII production and consequently cardiac repair. 4. Regulation of AngII on cardiac repair/remodeling postMI 4.1. Infarcted myocardium A paradigm of tissue repair has been proposed in which ACE and local AngII are integral to the orderly and sequential nature of repair that eventuates in fibrosis [33]. ACE is involved in a three-part de novo
generation of AngII within the repairing tissue that forms at the infarct site. The first component to local AngII generation is provided by activated macrophages. Following acute MI, ACE and AT1 receptor expressions are enhanced in the rat infarcted myocardium within a few days postMI and cells expressing ACE and AngII receptors are primarily macrophages in the early stage of repair [26,34]. These observations suggest that locally produced AngII may regulate the function of macrophages in an autocrine manner. One important role of macrophage is the removal of necrotic cellular debris. Additionally, macrophages initiate inflammatory response through activation of NF-κB. Redox sensitive NF-κB can be activated by reactive oxygen species (ROS) in the repairing tissue [18,35]. ROS in the infarcted myocardium is primarily produced by NADPH oxidase [36,37]. Current evidence suggests that AngII, through AT1-receptor activation, upregulates several subunits of this multienzyme complex, resulting in an increase in intracellular superoxide concentration in various pathological conditions [38,39]. Macrophage-derived NADPH oxidase expression (mRNA and protein) is markedly increased in the infarcted myocardium (Fig. 3), which is mostly evident in the first 2 weeks postMI and is co-localized with enhanced ACE and AT1 receptors. AT1 receptor antagonist (AT1Ra) is shown to suppress NADPH oxidase activity, which in turn suppresses ROS levels in the infarcted myocardium [36]. Elevated NADPH oxidase in the infarcted myocardium spatially coexists with activated NF-κB and enhanced expression of TNF-α, intercellular or vascular cell adhesion molecule (ICAM-1, VCAM-1) and monocyte chemoattractant protein (MCP)-1 (Fig. 3) [15]. On the whole, these studies indicate that AngII promotes cardiac inflammatory response through enhancing ROS production, which in turn, activates NF-κB and its downstream inflammatory cascade. The second component to local AngII generation is provided by endothelial cells. Vascular endothelial cells express AT1 receptors and high level of ACE, suggesting the potential regulation of AngII on local endothelial cell growth and function. Following acute MI, myocytes/ interstitial cells and existing blood vessels in the infarcted myocardium undergo necrosis, triggering cardiac angiogenesis. Newly formed vessels are seen first in the border zones as early as 3 days postMI and then extend into the infarcted myocardium. A considerable body of evidence has indicated that AngII stimulates angiogenesis in various diseases [40]. It has been shown that ACE inhibitor (ACEI) or AT1Ra inhibits angiogenesis in tumors [41]. In another report, the impaired angiogenesis in response to hindlimb ischemia is observed in AT1 receptor knockout mice [42]. Furthermore, angiogenesis is impaired by AT1 receptor blockade in cardiomyopathic hamster hearts [43]. The AngII-induced angiogenesis is mediated through the activation of VEGF and fibroblast growth factor-related pathways and of the inflammatory process [44,45]. However, the role of AngII on angiogenesis in the infarcted myocardium postMI is contradictory. Toko et al. [46] have shown that less neovascularization and inflammatory cell infiltration are induced in AT1 receptordeficient mice compared with wild type mice after MI, supporting that AngII upregulates cardiac angiogenesis. On the other hand, cardiac microvessel density following MI is decreased when the AT1 receptor is overexpressed [47], indicating that AngII suppresses cardiac angiogenesis in the infarcted heart. Thereby, further studies are required to clarify the potential role of AngII on angiogenesis in the infarcted myocardium. The underlying mechanisms should be also explored if AngII is determined to be an angiogenic factor. The third component to local AngII generation is provided by myoFb. MyoFb are the major cells expressing ACE and AT1 receptors
Fig. 3. Cardiac NADPH oxidase, TNF-α, ICAM-1, MCP-1, TGF-β1 and type I collagen gene expression. Compared to normal heart (panel A), NADPH oxidase mRNA (gp91phox subunit) is largely increased in the infarcted heart at week 1, particularly at the site of MI (panel B). TNF-α mRNA is markedly elevated in the infarcted heart at week 1 postMI (panel D), compared to the control heart (panel C). Elevated gene expression of ICAM-1 (panel E) and MCP-1 (panel F) is observed in the infarcted myocardium in the early stage of MI. Compared to the normal heart (panel G), TGF-β1 mRNA is markedly increased in both infarcted and noninfarcted myocardium at week 2 postMI (panel H). Type 1 collagen mRNA shows a similar pattern in the normal (panel I) and infarcted heart (panel J).
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in the fibrogenic stage of cardiac repair following MI [6,29]. In the infarcted myocardium, high levels of ACE and AT1 receptor expressions are spatially and temporally coincident with myoFb together with expression of TGF-β1 mRNA and TGF-β receptors, type I collagen mRNAs (Fig. 3), and collagen accumulation. Studies have demonstrated that cardiac AngII advances scar formation in the infarcted myocardium by stimulating TGF-β1 expression in transcription level, which, in turn, promotes myoFb differentiation/proliferation and collagen synthesis [22]. Our previous study has shown that treatment of AT1Ra, losartan, significantly reduces TGF-β1 mRNA levels in the infarcted myocardium [22]. Thus, myoFb-derived AngII stimulates fibrogenesis in the infarcted myocardium in an autocrine manner and facilitates scar formation. Taken together, the previous studies have shown that enhanced cardiac AngII production is involved in cardiac repair in the infarcted myocardium. Mediated by AT1 receptors, AngII promotes the scar formation by inducing inflammatory/fibrogenic responses, possibly angiogenesis as well. Fibrous tissue that forms at the site of cardiomyocyte loss preserves structural integrity and is integral to the heart's recovery. Thus, AngII facilitates cardiac repair. However, AngII-induced ROS production and inflammatory response may cause further cardiac damage at the border zone, thus expanding infarct size. ACEI and AT1Ra begun at or close to the onset of MI have each reduces infarct size, infarct expansion and hydroxyproline concentration at the infarct site [48,49]. On the other hand, deletion of AngII receptors reduces inflammatory cell infiltration in the infarcted myocardium [46], which may delay or impair scar formation. AngII, as a result, exerts both beneficial and harmful effects in cardiac repair following MI. The relative contribution of AT2 receptors in cardiac repair/ remodeling remains not completely understood. Our study has shown that increased AngII receptors in the infarcted rat myocardium are primarily the AT1 subtype, while AT2 receptors are barely detectable [26]. However, studies have shown that AT2 receptor deficiency exacerbates short-term death rates and heart failure after experimental MI in mice [50]. Other studies have also revealed that AT2 receptors exert an opposing effect on AT1 receptors. For example, AT2 receptors inhibit cell proliferation and reverse AT1 receptor-mediated hypertrophy [51]. Further studies are required to better understand the importance of AT2 receptors in cardiac remodeling, particularly in man. Accumulating evidence suggests that Ang(1–7) may play a role in counteracting the pressor, proliferative, and profibrotic actions of AngII in the heart. Development of heart failure subsequent to MI leads to increased expression of Ang(1–7), which was restricted to myocytes [52]. However, the importance of Ang(1–7) on cardiac repair/remodeling remains to be elucidated. 4.2. Noninfarcted myocardium In addition to cardiac repair in the infarcted myocardium, structural remodeling also appears in noninfarcted myocardium in the form of interstitial fibrosis and hypertrophy. The regulation of AngII on cardiac hypertrophy following MI has been reviewed elsewhere and will not be discussed in this review. Unlike cardiac repair that occurs right after MI, cardiac remodeling in the noninfarcted myocardium is slowly developed and begins to appear several weeks postMI. Interstitial fibrosis increases cardiac stiffness and contributes to ventricular dysfunction in the late stage of MI. The involvement of AngII in the development of cardiac remodeling in noninfarcted myocardium is recognized through the beneficial effect of chronic administration of ACEI and AT1Ra. ACE level and AT1 receptors are found to be significantly increased in the noninfarcted myocardium several weeks postMI. Cells expressing ACE in noninfarcted myocardium are primarily endothelial cells, while AT1 receptors are expressed by various cell types, including fibroblasts, vascular cells
and myocytes, suggesting an autocrine/paracrine function of AngII in cardiac structural remodeling. In contrast, macrophages and myoFb, which primarily contribute to local AngII production and cardiac repair in the infarcted myocardium are not evident in the noninfarcted myocardium. Thus, different cells and mechanisms are involved in AngII-induced fibrosis in the infarcted and noninfarcted myocardium. ACEI and AT1Ra have been proven effective in modulating the process of remodeling and in reducing the occurrence of adverse events in heart failure. Chronic treatment with ACEI decreased the expected fibrosis in the noninfarcted myocardium [53] and the proliferation of fibroblasts and endothelial cells following MI. Blockade of ACE or AngII receptors has also been shown to significantly reduce TGF-β1 expression, which in turn suppresses fibrous tissue formation in the noninfarcted myocardium [22]. Suppressed cardiac remodeling by AngII blockade has been found to significantly improve cardiac function and survival [54]. However, ACEI and AT1Ra treatment can not totally prevent the noninfarcted myocardium from the development of structural remodeling. This might be due to the fact that AngII is not the sole factor inducing cardiac structural remodeling. Other factors, such as endothelin, MMP/TIMP ratio, aldosterone, etc., also contribute to the process postMI. These favorable tissue protective effects of ACEI or AT1Ra are not confined to the infarcted heart. These interventions prevent the appearance of fibrosis in diverse organs with experimentally induced or naturally occurring tissue injury in circumstances in which the circulating RAS is not activated. These include: renal fibrosis [55] and lung fibrosis [56]. Attenuation of fibrous tissue formation by these interventions in diverse organs with various forms of injury supports the importance of local AngII in promoting fibrosis. 5. Summary and future directions The present review has focused on the activation of cardiac RAS following acute MI and the regulatory role of AngII on cardiac repair/ remodeling following MI. AngII exerts both salutary and deleterious effects on the infarcted myocardium. It stimulates inflammatory/ fibrogenic responses and possibly angiogenesis, thus promoting scar formation. On the other hand, AngII-induced ROS production may further damage myocardium in the border zones and enlarge infarct size. In the noninfarcted myocardium, AngII stimulates interstitial fibrosis and hypertrophy, which contributes to the development of ventricular dysfunction in the late stage of MI. ACEI and AT1Ra have been demonstrated to reduce structural remodeling and improve cardiac function and survival in animals and humans with MI. However, several concepts on cardiac RAS remain not fully understood. Firstly, the mechanism(s) that trigger the activation of cardiac RAS following MI remain to be elucidated. Furthermore, factors activating RAS in the infarcted and noninfarcted myocardium are likely different, which requires further investigation. Secondly, it has been reported that Ang(1–7) content is increased in the infarcted heart. However, the potential regulation of ACE2 and Ang(1–7) in cardiac remodeling remains uncertain and needs to be explored. Thirdly, the expression of AT2 receptors and their interaction with AT1 receptors in the human heart remain unknown. Further studies are essential to determine whether AT2 receptors play a protective role in the human infarcted heart. Acknowledgments This work was supported by NIH Heart, Blood and Lung Institute (RO1-HL67888 and RO1-HL077668, Yao Sun). References [1] Ferrario CM, Trask AJ, Jessup JA. Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1-7) in regulation of cardiovascular function. Am J Physiol Heart Circ Physiol 2005;289:H2281–90.
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[31] Ratajska A, Campbell SE, Sun Y, Weber KT. Angiotensin II associated cardiac myocyte necrosis: role of adrenal catecholamines. Cardiovasc Res 1994;28:684–90. [32] Sun Y, Ratajska A, Zhou G, Weber KT. Angiotensin-converting enzyme and myocardial fibrosis in the rat receiving angiotensin II or aldosterone. J Lab Clin Med 1993;122:395–403. [33] Lijnen PJ, Petrov VV. Role of intracardiac renin–angiotensin–aldosterone system in extracellular matrix remodeling. Methods Find Exp Clin Pharmacol 2003;25: 541–64. [34] Sun Y, Cleutjens JP, Diaz-Arias AA, Weber KT. Cardiac angiotensin converting enzyme and myocardial fibrosis in the rat. Cardiovasc Res 1994;28:1423–32. [35] Takahashi M, Suzuki E, Takeda R, Oba S, Nishimatsu H, Kimura K, et al. Angiotensin II and tumor necrosis factor-alpha synergistically promote monocyte chemoattractant protein-1 expression: roles of NF-kappaB, p38, and reactive oxygen species. Am J Physiol Heart Circ Physiol 2008;294:H2879–88. [36] Lu L, Quinn MT, Sun Y. Oxidative stress in the infarcted heart: role of de novo angiotensin II production. Biochem Biophys Res Commun 2004;325:943–51. [37] Sirker A, Zhang M, Murdoch C, Shah AM. Involvement of NADPH oxidases in cardiac remodelling and heart failure. Am J Nephrol 2007;27:649–60. [38] Agarwal R, Campbell RC, Warnock DG. Oxidative stress in hypertension and chronic kidney disease: role of angiotensin II. Semin Nephrol 2004;24:101–14. [39] Wolf G. Free radical production and angiotensin. Curr Hypertens Rep 2000;2: 167–73. [40] Heffelfinger SC. The renin angiotensin system in the regulation of angiogenesis. Curr Pharm Des 2007;13:1215–29. [41] Fujita M, Hayashi I, Yamashina S, Itoman M, Majima M. Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis. Biochem Biophys Res Commun 2002;294:441–7. [42] Sasaki K, Murohara T, Ikeda H, Sugaya T, Shimada T, Shintani S, et al. 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Contents lists available at ScienceDirect
Journal of Molecular and Cellular Cardiology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y j m c c
Review article
Intracardiac renin–angiotensin system and myocardial repair/remodeling following infarction Yao Sun ⁎ Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, 956 Court Ave. Rm B324A, Memphis, TN 38163, USA
a r t i c l e
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Article history: Received 4 May 2009 Received in revised form 29 July 2009 Accepted 4 August 2009 Available online 12 August 2009 Keywords: Myocardial infarction Cardiac repair Cardiac remodeling Cardiac RAS Ventricular dysfunction
a b s t r a c t The circulating renin-angiotensin system (RAS) is a classic endocrine system that regulates cardiovascular homeostasis during physiologic and pathologic states. Accumulated evidence has shown the presence of components of RAS in various tissues, which are upregulated in certain pathological conditions. Locally produced angiotensin (Ang)II may play an important role in tissue repair/remodeling in autocrine and/or paracrine manners. Following acute myocardial infarction (MI), cardiac repair occurs in the infarcted myocardium and structural remodeling is developed in noninfarcted myocardium, which are accompanied by activated cardiac RAS. In this review, the current understanding of independent activation of cardiac RAS and its regulation in the pathogenesis of myocardial repair/remodeling after MI is discussed. © 2009 Elsevier Ltd. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . Cardiac repair/remodeling following infarction . . . . . . . 2.1. Infarcted myocardium . . . . . . . . . . . . . . . . 2.2. Noninfarcted myocardium . . . . . . . . . . . . . . 3. Activation of cardiac angiotensin system in the infarcted heart 4. Regulation of AngII on cardiac repair/remodeling postMI . . . 4.1. Infarcted myocardium . . . . . . . . . . . . . . . . 4.2. Noninfarcted myocardium . . . . . . . . . . . . . . 5. Summary and future directions . . . . . . . . . . . . . . . Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction The critical role of the circulating RAS in the regulation of arterial pressure and sodium homeostasis has been recognized for many years. AngII is the most powerful biologically active product of the RAS. AngII directly constricts vascular smooth muscle cells, enhances myocardial contractility, stimulates aldosterone production, stimulates release of catecholamines from the adrenal medulla and sympathetic nerve endings, increases sympathetic nervous system activity, and stimulates thirst and salt appetite. AngII also regulates sodium transport by epithelial cells in the intestine and kidney.
⁎ Tel./fax: +1 901 448 4921. E-mail address: [email protected]. 0022-2828/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.yjmcc.2009.08.002
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RAS is a coordinated hormonal cascade. Renin acts on the circulating precursor angiotensinogen to form AngI. AngI has no biological activity and is converted to AngII by endothelial angiotensin-converting enzyme (ACE). The actions of AngII are mediated by specific membrane-bound AngII type-1 (AT1) and type-2 (AT2) receptors with the majority of cardiovascular actions of AngII are mediated by the AT1 receptors. AT2 receptors induce a counterregulatory vasodilatation that is largely mediated by bradykinin and nitric oxide. AngII has a very short half-life and is quickly degraded to active AngIII and Ang(1–7) and inactive fragments. AngIII has actions similar to those of AngII. Ang(1–7), via Mas receptors, exerts the hypotensive action through the release of bradykinin, prostaglandins, and endothelial nitric oxide [1]. Thus, Ang(1–7) acts as an endogenous inhibitor of AngII. ACE2 is the newest member of the RAS [1]. ACE2 is primarily expressed in endothelial cells in the heart and kidney. It
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hydrolyzes AngII to Ang(1–7) and its enzymatic activity is not affected by ACE inhibitors. There has also been a growing appreciation of the organ-specific roles exerted by AngII acting as an autocrine/paracrine factor. Local AngII production is activated in various pathological states, such as atherosclerosis [2], various injured tissues [3], hypertensive and diabetic kidney [4,5], MI [6,7], etc. AngII has been demonstrated to stimulate inflammation, cell growth, apoptosis, fibrogenesis, and differentiation, regulates the gene expression of bioactive substances, and activates multiple intracellular signaling pathways, all of which might contribute to tissue repair/remodeling [8,9]. Following MI, structural changes appear in both the infarcted and noninfarcted myocardium. Cardiac repair occurs in the infarcted myocardium, which is associated with an inflammatory reaction, angiogenesis and scar formation. Structural remodeling in the noninfarcted myocardium includes hypertrophy and interstitial fibrosis [10–12]. Fibrous tissue that forms at the site of cardiomyocyte loss preserves structural integrity and is integral to the heart's recovery, whereas structural remodeling of viable myocardium impairs tissue behavior. Substances involved in cardiac repair/remodeling are of considerable interest and an important clinical issue. Multiple factors may, in fact, contribute to left ventricular remodeling at different stages
postMI. There is growing recognition and experimental evidence that cardiac RAS is activated following MI and locally produced AngII plays a central role in the pathogenesis of myocardial repair/remodeling after MI. This review will in particular address the regulation of locally produced AngII in promoting cardiac repair/remodeling following MI. 2. Cardiac repair/remodeling following infarction 2.1. Infarcted myocardium A highly regulated process of cardiac repair follows the necrotic loss of cardiomyocytes after MI. It begins with the activation of matrix metalloproteinases (MMPs), which degrade the existing extracellular matrix and coronary vasculature in the infarcted myocardium [13,14]. This proteolytic activity declines by the end of week 1 postMI [13,14]. Circulating leukocytes infiltrate into the infarct site soon after MI, while monocyte-derived macrophages are the major population of inflammatory cells in the infarcted myocardium (Fig. 1). The leukocytes home to the site of MI drawn by adhesion molecules and chemokines expressed by the endothelial cells of the coronary vasculature that borders on the infarct site [15,16]. Their migration into the infarct site is facilitated by MMP proteolytic activity.
Fig. 1. Cardiac fibrosis and cells responsible for cardiac repair postMI: Following MI, abundant ED-1+ macrophages appear in the infarcted myocardium at week 1 (panel A, brown), while the population of neutrophils and lymphocytes is low (not shown). Interstitial α-SMA+ myoFb are not present in the normal myocardium (panel B, arrows: blood vessels). Following MI, myoFb (brown) are accumulated in the infarcted myocardium at week 1 and located primarily around necrotic tissue (Nec) (panel C). Normal myocardium contains a small amount of collagen (red, picrosirius red staining) in the interstitial space (panel D). Following MI, scar is formed in the infarcted myocardium (panel E) and interstitial fibrosis (panel F) is developed in the noninfarcted myocardium at 4 weeks postMI.
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Inflammatory response in the infarcted myocardium involves the coordinated activation of a series of cytokine and adhesion molecule genes. A critical element in the regulation of these genes involves nuclear factor-kappa B (NF-κB), which triggers gene expression of proinflammatory cytokines, initiating an inflammatory response [17]. In rodent models of MI, NF-κB is activated primarily in macrophages of infarcted myocardium [18], which is accompanied with upregulated TNF-α expression and inflammatory response, including inflammatory protein synthesis, macrophage phagocytosis, cell growth, differentiation and apoptosis [18,19]. Macrophages also release angiogenic promoters, such as vascular endothelial growth factor (VEGF) [20,21], triggering angiogenesis in the infarcted myocardium. The inflammatory response and angiogenesis peak at weeks 1 and 2 postMI and then taper off. Inflammatory cells disappear from the infarct site within 2–3 weeks after MI, a consequence of their programmed cell death, while cardiac angiogenesis becomes quiescent when the healing is completed. The inflammatory response and angiogenesis are the vitally necessary mechanisms of healing of injured myocardium. These processes remove damaged/necrotic tissue, establish a vascular supply to support repair, and stimulate scar formation. However, an exuberant inflammatory response has a direct deleterious effect on myocyte, leading further myocardial damage in the border zones and thus expanding infarct size in the animal experiments. However, in human trials, none of the applied anti-inflammatory medications reached a convincing clinical impact. These observations emphasize the need for better understanding of the cellular and molecular events associated with the inflammatory response in order to achieve effective suppression of injurious processes without interfering with healing and cardiac repair. The fibrogenic component, which substitutes for lost parenchymal cells, follows the initial phase of collagen degradation. It begins with
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the activation of transforming growth factor (TGF)-β1 [22], the key mediator of fibrogenesis, released primarily by inflammatory cells. Increased synthesis of fibrillar type III and type I collagens is preceded by an increased expression of their mRNA transcripts [12]. Collagen fibers are morphologically evident at week 1 postMI, while an organized assembly of these fibers in the form of scar tissue becomes evident at week 2. This assembly continues to accumulate in the following weeks (Fig. 1). Cells responsible for fibrous tissue formation at the site of MI are phenotypically transformed fibroblasts, myofibroblasts (MyoFb) (Fig. 1) [23]. MyoFb appear at the infarct site soon after the arrival of inflammatory cells [6]. Cells that account for the appearance of myoFb have been demonstrated to include interstitial fibroblasts, pericytes, macrophages, or circulating bone marrow-derived progenitor cells that transdifferentiate at the infarct site. Specific factors that facilitate this differentiation process have been identified. It is presumed that TGF-β1, elaborated by macrophages, governs the appearance of the myoFb phenotype [24]. After appearance, MyoFb rapidly proliferate and are responsible for formation of the scar via their expression of type I and III fibrillar collagens at both mRNA and protein levels [12,22]. The number of MyoFb is gradually declined from the scar tissue through apoptosis after cardiac repair is completed. 2.2. Noninfarcted myocardium Interstitial fibrosis is developed in the noninfarcted myocardium, particularly in the heart with large MI (Fig. 1). It is observed in the absence of cell loss. TGF-β1 level and collagen synthesis is enhanced in the noninfarcted myocardium within several weeks postMI [12,22]. Fibrous tissue accumulation is observed in the noninfarcted myocardium in the rat heart with extensive MI [12]. Perivascular fibrosis of intramyocardial coronary arteries is also seen at the site. Cells
Fig. 2. Autoradiographic ACE and AngII receptor binding: In the normal heart, a low density of ACE binding is present in the left and right ventricle (LV, RV), while blood vessels express higher levels of ACE (bright spots) (panel A). Following MI, ACE binding is largely increased in the infarcted myocardium (MI) at week 1 (panel B) and in following weeks (not shown). ACE is also increased in the noninfarcted myocardium, but to a much lesser extent compared to the infarcted myocardium (panel B). Normal heart contains low level of AngII receptors (panel C). AngII receptor binding is markedly increased, particularly in the infarcted myocardium at week 1 (panel D) and remains elevated over the course of 4 weeks (not shown). S: septum.
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contributing to fibrosis in the noninfarcted myocardium are primarily interstitial fibroblasts. MyoFb are not observed in the noninfarcted myocardium and are not responsible for the development of interstitial fibrosis. Interstitial fibrosis can enhance myocardial stiffness and contributes to ventricular dysfunction. Mechanisms responsible for the appearance of interstitial fibrosis in noninfarcted myocardium are, however, not fully understood. It may involve either a direct effect of stretch and/or a diffusion of fibrogenic mediators that originate in the infarcted myocardium through the interstitial space. 3. Activation of cardiac angiotensin system in the infarcted heart Renin expression (mRNA and protein) is undetectable in the normal rat myocardium, indicating that renin is not produced in the normal heart [7,25]. Following experimental MI, renin expression is significantly increased in the infarcted rat myocardium and cells expressing renin are primarily macrophages and myofibroblasts, demonstrating that renin is synthesized in the infarcted heart [7,25]. Other studies, however, suggest that cardiac renin and AngI can be taken up from the circulation. Low ACE levels are present throughout the myocardium of the right and left atria and ventricles of the normal adult rat heart, as is also the case for AngII receptors. ACE and AT1 receptor expressions are significantly increased at the infarcted myocardium (Fig. 2), coincident with inflammatory response, angiogenesis and the accumulation of fibrillar collagen [6,26]. Moreover, elevated AngII concentration is found at the infarct site [27]. In the infarcted myocardium, ACE is expressed by endothelial cells of the neovasculature, macrophages and myoFb [6,28]; and AT1 receptors primarily by macrophages, myoFb and vascular smooth muscle cells [29]. The expression of ACE and AT1 receptors in macrophages and myoFb in the infarcted myocardium suggest that locally generated AngII plays a role in inflammatory and fibrogenic reactions in an autocrine manner, which is mediated by AT1 receptors. ACE level is also found significantly increased in the noninfarcted myocardium, but to a much lesser extent compared to the infarcted myocardium [6]. The activation of cardiac RAS following MI is, however, not often accompanied by elevated circulating RAS in the early stage of MI [30], suggesting that RAS activation in the repairing myocardium is independent of circulating RAS. Cardiac dysfunction with activated circulating RAS is mostly developed in the later stage of MI (N4 weeks). Nonischemic models of cardiac repair have also been examined relative to high ACE expression, including AngII infusion via an implanted mini-pump [31]; administration of isoproterenol, a synthetic catecholamine [3]; and chronic (N3 weeks) administration of aldosterone by mini-pump in uninephrectomized rats on a high salt diet [32]. At each site of nonischemic cardiac repair, and irrespective of its etiologic basis, the temporal and spatial appearance of high levels of ACE expression is coincident with inflammatory response and fibrous tissue formation that resembles reparative responses observed with ischemic necrosis following MI. Thus, regardless of the etiologic basis of cardiac injury, ACE appears at sites of cardiac repair and contributes to local AngII production and consequently cardiac repair. 4. Regulation of AngII on cardiac repair/remodeling postMI 4.1. Infarcted myocardium A paradigm of tissue repair has been proposed in which ACE and local AngII are integral to the orderly and sequential nature of repair that eventuates in fibrosis [33]. ACE is involved in a three-part de novo
generation of AngII within the repairing tissue that forms at the infarct site. The first component to local AngII generation is provided by activated macrophages. Following acute MI, ACE and AT1 receptor expressions are enhanced in the rat infarcted myocardium within a few days postMI and cells expressing ACE and AngII receptors are primarily macrophages in the early stage of repair [26,34]. These observations suggest that locally produced AngII may regulate the function of macrophages in an autocrine manner. One important role of macrophage is the removal of necrotic cellular debris. Additionally, macrophages initiate inflammatory response through activation of NF-κB. Redox sensitive NF-κB can be activated by reactive oxygen species (ROS) in the repairing tissue [18,35]. ROS in the infarcted myocardium is primarily produced by NADPH oxidase [36,37]. Current evidence suggests that AngII, through AT1-receptor activation, upregulates several subunits of this multienzyme complex, resulting in an increase in intracellular superoxide concentration in various pathological conditions [38,39]. Macrophage-derived NADPH oxidase expression (mRNA and protein) is markedly increased in the infarcted myocardium (Fig. 3), which is mostly evident in the first 2 weeks postMI and is co-localized with enhanced ACE and AT1 receptors. AT1 receptor antagonist (AT1Ra) is shown to suppress NADPH oxidase activity, which in turn suppresses ROS levels in the infarcted myocardium [36]. Elevated NADPH oxidase in the infarcted myocardium spatially coexists with activated NF-κB and enhanced expression of TNF-α, intercellular or vascular cell adhesion molecule (ICAM-1, VCAM-1) and monocyte chemoattractant protein (MCP)-1 (Fig. 3) [15]. On the whole, these studies indicate that AngII promotes cardiac inflammatory response through enhancing ROS production, which in turn, activates NF-κB and its downstream inflammatory cascade. The second component to local AngII generation is provided by endothelial cells. Vascular endothelial cells express AT1 receptors and high level of ACE, suggesting the potential regulation of AngII on local endothelial cell growth and function. Following acute MI, myocytes/ interstitial cells and existing blood vessels in the infarcted myocardium undergo necrosis, triggering cardiac angiogenesis. Newly formed vessels are seen first in the border zones as early as 3 days postMI and then extend into the infarcted myocardium. A considerable body of evidence has indicated that AngII stimulates angiogenesis in various diseases [40]. It has been shown that ACE inhibitor (ACEI) or AT1Ra inhibits angiogenesis in tumors [41]. In another report, the impaired angiogenesis in response to hindlimb ischemia is observed in AT1 receptor knockout mice [42]. Furthermore, angiogenesis is impaired by AT1 receptor blockade in cardiomyopathic hamster hearts [43]. The AngII-induced angiogenesis is mediated through the activation of VEGF and fibroblast growth factor-related pathways and of the inflammatory process [44,45]. However, the role of AngII on angiogenesis in the infarcted myocardium postMI is contradictory. Toko et al. [46] have shown that less neovascularization and inflammatory cell infiltration are induced in AT1 receptordeficient mice compared with wild type mice after MI, supporting that AngII upregulates cardiac angiogenesis. On the other hand, cardiac microvessel density following MI is decreased when the AT1 receptor is overexpressed [47], indicating that AngII suppresses cardiac angiogenesis in the infarcted heart. Thereby, further studies are required to clarify the potential role of AngII on angiogenesis in the infarcted myocardium. The underlying mechanisms should be also explored if AngII is determined to be an angiogenic factor. The third component to local AngII generation is provided by myoFb. MyoFb are the major cells expressing ACE and AT1 receptors
Fig. 3. Cardiac NADPH oxidase, TNF-α, ICAM-1, MCP-1, TGF-β1 and type I collagen gene expression. Compared to normal heart (panel A), NADPH oxidase mRNA (gp91phox subunit) is largely increased in the infarcted heart at week 1, particularly at the site of MI (panel B). TNF-α mRNA is markedly elevated in the infarcted heart at week 1 postMI (panel D), compared to the control heart (panel C). Elevated gene expression of ICAM-1 (panel E) and MCP-1 (panel F) is observed in the infarcted myocardium in the early stage of MI. Compared to the normal heart (panel G), TGF-β1 mRNA is markedly increased in both infarcted and noninfarcted myocardium at week 2 postMI (panel H). Type 1 collagen mRNA shows a similar pattern in the normal (panel I) and infarcted heart (panel J).
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in the fibrogenic stage of cardiac repair following MI [6,29]. In the infarcted myocardium, high levels of ACE and AT1 receptor expressions are spatially and temporally coincident with myoFb together with expression of TGF-β1 mRNA and TGF-β receptors, type I collagen mRNAs (Fig. 3), and collagen accumulation. Studies have demonstrated that cardiac AngII advances scar formation in the infarcted myocardium by stimulating TGF-β1 expression in transcription level, which, in turn, promotes myoFb differentiation/proliferation and collagen synthesis [22]. Our previous study has shown that treatment of AT1Ra, losartan, significantly reduces TGF-β1 mRNA levels in the infarcted myocardium [22]. Thus, myoFb-derived AngII stimulates fibrogenesis in the infarcted myocardium in an autocrine manner and facilitates scar formation. Taken together, the previous studies have shown that enhanced cardiac AngII production is involved in cardiac repair in the infarcted myocardium. Mediated by AT1 receptors, AngII promotes the scar formation by inducing inflammatory/fibrogenic responses, possibly angiogenesis as well. Fibrous tissue that forms at the site of cardiomyocyte loss preserves structural integrity and is integral to the heart's recovery. Thus, AngII facilitates cardiac repair. However, AngII-induced ROS production and inflammatory response may cause further cardiac damage at the border zone, thus expanding infarct size. ACEI and AT1Ra begun at or close to the onset of MI have each reduces infarct size, infarct expansion and hydroxyproline concentration at the infarct site [48,49]. On the other hand, deletion of AngII receptors reduces inflammatory cell infiltration in the infarcted myocardium [46], which may delay or impair scar formation. AngII, as a result, exerts both beneficial and harmful effects in cardiac repair following MI. The relative contribution of AT2 receptors in cardiac repair/ remodeling remains not completely understood. Our study has shown that increased AngII receptors in the infarcted rat myocardium are primarily the AT1 subtype, while AT2 receptors are barely detectable [26]. However, studies have shown that AT2 receptor deficiency exacerbates short-term death rates and heart failure after experimental MI in mice [50]. Other studies have also revealed that AT2 receptors exert an opposing effect on AT1 receptors. For example, AT2 receptors inhibit cell proliferation and reverse AT1 receptor-mediated hypertrophy [51]. Further studies are required to better understand the importance of AT2 receptors in cardiac remodeling, particularly in man. Accumulating evidence suggests that Ang(1–7) may play a role in counteracting the pressor, proliferative, and profibrotic actions of AngII in the heart. Development of heart failure subsequent to MI leads to increased expression of Ang(1–7), which was restricted to myocytes [52]. However, the importance of Ang(1–7) on cardiac repair/remodeling remains to be elucidated. 4.2. Noninfarcted myocardium In addition to cardiac repair in the infarcted myocardium, structural remodeling also appears in noninfarcted myocardium in the form of interstitial fibrosis and hypertrophy. The regulation of AngII on cardiac hypertrophy following MI has been reviewed elsewhere and will not be discussed in this review. Unlike cardiac repair that occurs right after MI, cardiac remodeling in the noninfarcted myocardium is slowly developed and begins to appear several weeks postMI. Interstitial fibrosis increases cardiac stiffness and contributes to ventricular dysfunction in the late stage of MI. The involvement of AngII in the development of cardiac remodeling in noninfarcted myocardium is recognized through the beneficial effect of chronic administration of ACEI and AT1Ra. ACE level and AT1 receptors are found to be significantly increased in the noninfarcted myocardium several weeks postMI. Cells expressing ACE in noninfarcted myocardium are primarily endothelial cells, while AT1 receptors are expressed by various cell types, including fibroblasts, vascular cells
and myocytes, suggesting an autocrine/paracrine function of AngII in cardiac structural remodeling. In contrast, macrophages and myoFb, which primarily contribute to local AngII production and cardiac repair in the infarcted myocardium are not evident in the noninfarcted myocardium. Thus, different cells and mechanisms are involved in AngII-induced fibrosis in the infarcted and noninfarcted myocardium. ACEI and AT1Ra have been proven effective in modulating the process of remodeling and in reducing the occurrence of adverse events in heart failure. Chronic treatment with ACEI decreased the expected fibrosis in the noninfarcted myocardium [53] and the proliferation of fibroblasts and endothelial cells following MI. Blockade of ACE or AngII receptors has also been shown to significantly reduce TGF-β1 expression, which in turn suppresses fibrous tissue formation in the noninfarcted myocardium [22]. Suppressed cardiac remodeling by AngII blockade has been found to significantly improve cardiac function and survival [54]. However, ACEI and AT1Ra treatment can not totally prevent the noninfarcted myocardium from the development of structural remodeling. This might be due to the fact that AngII is not the sole factor inducing cardiac structural remodeling. Other factors, such as endothelin, MMP/TIMP ratio, aldosterone, etc., also contribute to the process postMI. These favorable tissue protective effects of ACEI or AT1Ra are not confined to the infarcted heart. These interventions prevent the appearance of fibrosis in diverse organs with experimentally induced or naturally occurring tissue injury in circumstances in which the circulating RAS is not activated. These include: renal fibrosis [55] and lung fibrosis [56]. Attenuation of fibrous tissue formation by these interventions in diverse organs with various forms of injury supports the importance of local AngII in promoting fibrosis. 5. Summary and future directions The present review has focused on the activation of cardiac RAS following acute MI and the regulatory role of AngII on cardiac repair/ remodeling following MI. AngII exerts both salutary and deleterious effects on the infarcted myocardium. It stimulates inflammatory/ fibrogenic responses and possibly angiogenesis, thus promoting scar formation. On the other hand, AngII-induced ROS production may further damage myocardium in the border zones and enlarge infarct size. In the noninfarcted myocardium, AngII stimulates interstitial fibrosis and hypertrophy, which contributes to the development of ventricular dysfunction in the late stage of MI. ACEI and AT1Ra have been demonstrated to reduce structural remodeling and improve cardiac function and survival in animals and humans with MI. However, several concepts on cardiac RAS remain not fully understood. Firstly, the mechanism(s) that trigger the activation of cardiac RAS following MI remain to be elucidated. Furthermore, factors activating RAS in the infarcted and noninfarcted myocardium are likely different, which requires further investigation. Secondly, it has been reported that Ang(1–7) content is increased in the infarcted heart. However, the potential regulation of ACE2 and Ang(1–7) in cardiac remodeling remains uncertain and needs to be explored. Thirdly, the expression of AT2 receptors and their interaction with AT1 receptors in the human heart remain unknown. Further studies are essential to determine whether AT2 receptors play a protective role in the human infarcted heart. Acknowledgments This work was supported by NIH Heart, Blood and Lung Institute (RO1-HL67888 and RO1-HL077668, Yao Sun). References [1] Ferrario CM, Trask AJ, Jessup JA. Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1-7) in regulation of cardiovascular function. Am J Physiol Heart Circ Physiol 2005;289:H2281–90.
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