- Email: [email protected]
Bradykinin in protection against leftventricular hypertrophy
COMMENTARY
expressed in calcified arterial lesions both in atherosclerosis and in the vascular disease associated with chronic renal failure.18,19 Among these are bone morphogenetic protein 2, osteocalcin, and bone sialoprotein. Recently Ahmed and colleagues9 used immunohistochemistry to demonstrate expression of the bone-matrix protein osteopontin in arterial tissues obtained from patients with CUA. Osteopontin expression was limited to vessels that contained calcium deposits but was absent in uncalcified vessels from the same individuals. Although a causative role for osteopontin cannot be inferred, the results suggest that selected bone-related proteins are involved either primarily or secondarily in the process of vascular calcification in renal failure. In this regard, the finding that warfarin affects the vascular calcification in laboratory animals may have direct clinical relevance.20 Mice with inactivating mutations in both alleles of the gene encoding matrix GLA protein (MGP) inappropriately calcify various cartilages, including the epiphyseal growth plate, leading to skeletal deformities and osteoporosis.21 More notably, the animals die several months after birth from haemorrhage due to the rupture of extensively calcified arteries. Such findings indicate that MGP has a fundamental physiological role as an inhibitor of calcification in vascular tissue. Pharmacological agents, such as warfarin, that inhibit MGP synthesis may, therefore, disrupt an important mechanism for preserving vascular integrity. Although not addressed specifically in the study by Mazhar and colleagues, seven of 19 (37%) of cases of CUA but only one of 54 (2%) of controls had been treated with warfarin.8 It may be prudent therefore to reassess the safety and suitability of warfarin as a means of preventing thrombosis in arteriovenous fistulas and grafts in patients undergoing haemodialysis to ensure that it does not aggravate the vascular calcification to which these patients are prone. What recent work has also indicated is that, apart from the risks traditionally associated with disturbances in mineral metabolism due to chronic renal failure, localised changes in the tissuespecific expression or function of various bone-related proteins such as osteopontin and MGP may also contribute to the development of CUA. William G Goodman Division of Nephrology, Department of Medicine, UCLA School of Medicine, Los Angeles, CA 9005, USA (e-mail: [email protected]) 1
2
3
4
5 6 7
8
Gipstein RM, Coburn JW, Adams JA, et al. Calciphylaxis in man: a syndrome of tissue necrosis and vascular calcification in 11 patients with chronic renal failure. Arch Intern Med 1976; 136: 1273–80. Conn J Jr, Krumlovsky FA, del Greco F, Simon NM. Calciphylaxis: etiology of progressive vascular calcification and gangrene? Ann Surg 1973; 177: 206–10. Androuge H, Frazier M, Zeluff B, Suki WN. Systemic calciphylaxis: successful treatment with parathyroidectomy. J Urol 1983; 129: 362–63. Fox R, Banowsky LH, Cruz AB, Jr. Post-renal transplant calciphylaxis: successful treatment with parathyroidectomy. J Urol 1983; 129: 362–63. Llach F. The evolving pattern of calciphylaxis: therapeutic considerations. Nephrol Dial Transplant 2001; 16: 448–51. Selye H, Gabbiani G, Strebel R. Sensitization to calciphylaxis by endogenous parathyroid hormone. Endocrinology 1962; 50: 554-58. Ruggian J, Maesaka J, Fishbane S. Proximal calciphylaxis in four insulin-requiring diabetic hemodialysis patients. Am J Kidney Dis 1996; 28: 409–14. Mazhar AR, Johnson RJ, Gillen D, et al. Risk factors and mortality associated with calciphylaxis in end-stage renal disease. Kidney Int 2001; 60: 324–32.
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Ahmed S, O’Neill KD, Hood AF, Evan AP, Moe SM. Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells. Am J Kidney Dis 2001; 37: 1267–76. Marchais SJ, Metivier F, Guerin AP, London GM. Association of hyperphosphataemia with haemodynamic disturbances in end-stage renal disease. Nephrol Dial Transplant 1999; 14: 2178–83. Guérin AP, London GM, Marchais SJ, Metivier F. Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 2000; 15: 1014–21. Goodman WG, Goldin J, Kuizon BD, et al. Coronary artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000; 342: 1478–83. Mawad HW, Sawaya BP, Sarin R, Malluche HH. Calcific uremic arteriolopathy in association with low turnover uremic bone disease. Clin Nephrol 1999; 52: 160–66. Salusky IB, Ramirez JA, Oppenheim WL, Gales B, Segre GV, Goodman WG. Biochemical markers of renal osteodystrophy in pediatric patients undergoing CAPD/CCPD. Kidney Int 1994; 45: 253–58. Hutchison AJ, Whitehouse RW, Freemont AJ, Adams JE, Mawer EB, Gokal R. Histological, radiological, and biochemical features of the adynamic bone lesion in continuous ambulatory peritoneal dialysis patients. Am J Nephrol 1994; 14: 19–29. Sherrard DJ, Hercz G, Pei Y, Segre G. The aplastic form of renal osteodystrophy. Nephrol Dial Transplant1996; 11 (suppl 3): 29–31. Zacharias JM, Fontaine B, Fine A. Calcium use increases risk of calciphylaxis: a case-control study. Perit Dial Int 1999; 19: 248–52. Shanahan CM, Proudfoot D, Tyson KL, Cary NR, Edmonds M, Weissberg PL. Expression of mineralisation-regulating proteins in association with human vascular calcification. Z Kardiol 2000; 89 (suppl 2): 63–68. Shanahan CM, Cary NR, Salisbury JR, Proudfoot D, Weissberg PL, Edmonds ME. Medial localization of mineralization-regulating proteins in association with Monckeberg’s sclerosis: evidence for smooth muscle cell-mediated vascular calcification. Circulation 1999; 100: 2168–76. Shanahan CM, Proudfoot D, Farzaneh-Far A, Weissberg PL. The role of Gla proteins in vascular calcification. Crit Rev Eukaryot Gene Expr 1998; 8: 357–75. Luo G, Ducy P, McKee MD, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 1997; 386: 78–81.
Bradykinin in protection against leftventricular hypertrophy See page 1155
Left-ventricular hypertrophy (LVH) substantially increases risk of sudden death and other cardiovascular complications even after adjustment for other known risk factors.1 On the basis of the pressor and remodelling effects of antiotensin II, the renin-angiotensin system is widely thought to play an important part in the development of LVH. The efficacy of angiotensinconverting-enzyme (ACE) inhibitors in lessening progressive left-ventricular (LV) remodelling and rates of sudden death in patients with left-ventricular dysfunction further underscores the potential importance this system. Understanding how the reninangiotensin system modulates the development of LVH is thus of clinical importance. The major components of the renin-angiotensin system are illustrated in the figure. ACE not only generates the biologically active peptide angiotensin II but also degrades bradykinin. Kinetic studies have shown that bradykinin is the preferred ACE substrate.2 Of the two angiotensin II receptors that have been identified, the type 1 (AT1) receptor mediates the classic pressor effects of angiotensin II, whereas the type 2 (AT2) receptor mediates hypotensive effects. The increasing number of human polymorphisms that have been identified provides new opportunities to define genetic contributions to common yet complex diseases such as LVH. Polymorphisms of all four of the
THE LANCET • Vol 358 • October 6, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
Renin-angiotensin system Angiotensinogen Renin
Degradation products Angiotensin I
Chymase
ACE
Angiotensin II
Bradykinin
ACE
AT1R
B2BKR
AT2R Cell
Enzymes are indicated in italics. Abbreviations used: AT1R=AT1 receptor; AT2R=AT2 receptor; B2BKR=B2 bradykinin receptor
genes for the renin-angiotensin system have been linked to the development of LVH.3 These polymorphisms are ACE deletion (D) or insertion (I), AT1 receptor A1166C, AT2 receptor G1675A, and angiotensinogen M235T. Several additional angiotensinogen gene polymorphisms (G-6A, T31C, and T174M) are in linkage dysequilibrium with M235T and have also been implicated.2 The best studied of these polymorphisms is the ACE D or I polymorphism that influences ACE concentrations and activity. The D allele is linked to increased ACE activity in a gene dose-dependent manner, and the DD genotype has been repeatedly (though not universally) associated with increased risk of LVH. How might the D allele increase the risk of developing LVH? Two answers have been proposed: increased generation of angiotensin II or increased degradation of bradykinin. Attempts to resolve this question have been confounded, however, by the clinical heterogeneity of patients with LVH. In normotensive individuals undergoing vigorous physical training, LV mass has been shown to increase predictably, so these people form a suitable population in which to study the effect of the ACE insertion/deletion polymorphism on LV growth. In a prospective study of healthy normotensive male army recruits about to start a physical training programme, Myerson and colleagues4 showed that the increase in LV growth during training correlated with the ACE insertion/deletion genotype—being greatest in men with the D/D genotype, intermediate in men with the D/I genotype, and lowest in men with the I/I genotype. They then made the critical observation that prophylactic treatment with the AT1-receptor antagonist losartan had no impact on LV growth, which suggested that the effect of the ACE insertion/deletion polymorphism on LV mass was most probably due to its effect on cardiac bradykinin concentrations. In today’s Lancet, David Brull and colleagues report on an extension of Myerson and colleagues’ study. They examined the effect of the +9/–9 B2 bradykinin receptor polymorphism. The B2 bradykinin receptor is stimulated by bradykinin, and the –9 allele has previously been shown to result in more B2 bradykinin-receptor mRNA than has the +9 allele.5 Brull and colleagues found that
THE LANCET • Vol 358 • October 6, 2001
LV growth during training correlated with gene dose of the +9 allele for the B2 bradykinin receptor, and that the ACE and bradykinin- receptor genotypes interacted additively. Thus individuals with the greatest increase in LV mass had the highest concentrations of ACE (D/D genotype) and the lowest concentrations of B2 bradykinin receptor (+9/+9 genotype). These results strongly support an important role for bradykinin in the ACE-mediated effect on LVH. All components of a functional bradykinin system are expressed in the heart, and bradykinin clearly mediates important cardiovascular effects, such as increased vascular permeability, enhanced myocardial glucose uptake, negative inotropism, and inhibition of myocardial growth.2,6 Many, but not all, of these effects are secondary to its ability to potently stimulate generation of autacoids, such as nitric oxide and prostaglandins. Bradykinin has been shown to play an integral part in protecting the ischaemic myocardium. Furthermore, transgenic rats overexpressing tissue kallikrein (a kinin-generating enzyme) develop less cardiac hypertrophy and fibrosis than do wild-type rats.7 Conversely, genetically ablating B2 bradykinin receptors results in enhanced salt-induced hypertension and hypertrophic cardiomyopathy.8 There is also considerable evidence supporting interactions between bradykinin and the reninangiotensin system. The ACE D allele has been shown to have a significant effect on the in-vivo degradation of bradykinin in human beings;9 and epicardial vasodilatory responses to intracoronary bradykinin administration were depressed in patients with the ACE D/D genotype.10 The cardioprotective effect of ACE inhibitors was lost in B2 bradykinin-receptor knock-out mice,11 and a B2 bradykinin-receptor antagonist significantly attenuated the antihypertensive of effect of ACE inhibitors in human beings.12 Additionally, ACE inhibitors have been shown to mediate cross-talk between membrane-bound ACE and B2 bradykinin receptors, which resulted in enhanced bradykinin activity due to prevention of receptor desensitisation.13,14 It now seems probable that bradykinin is an important participant in the cardiac effects of the renin-angiotensin system; and novel pharmaceutical approaches to further increase cardiac bradykinin concentrations may be clinically beneficial. Additional studies, however, need to clarify whether the processes found in exercise-induced LV growth in normotensive people also occur in pathological LVH. It is important also to recognise that the ACE and B2 bradykinin-receptor polymorphisms account for only a fraction of the total variability in the expression of LVH. A complete understanding of LVH variability is certain to be extremely complex, involving multiple gene interactions as well as gene-environment interactions. Brull and colleagues’ findings are, however, an important first step in the unravelling of the relation between ACE activity, bradykinin, and LVH. Bruce Zuraw Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA 92037, USA (e-mail: [email protected])
1
2 3
Lorell BH, Carabello BA. Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation 2000; 102: 470–79. Dell’Itlalia, LJ, Oparil S. Bradykinin in the heart: friend or foe? Circulation 1999; 100: 2305–07. Wang J-G, Staessen JA. Genetic polymorphisms in the renin-
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COMMENTARY
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angiotensin system: relevance for susceptibility to cardiovascular disease. Eur J Pharmacol 2000; 410: 289–302. Myerson SG, Montgomery HE, Whittingham M, et al. Left ventricular hypertrophy with exercise and ACE gene insertion/deletion polymorphism: a randomized controlled trial with losartan. Circulation 2001; 103: 226–30. Lung CC, Chan EK, Zuraw BL. Analysis of an exon 1 polymorphism of the B2 bradykinin receptor gene and its transcript in normal subjects and patients with C1 inhibitor deficiency. J Allergy Clin Immunol 1997; 99: 134–46. Linz W, Wiemer G, Gohlke P, Unger T, Scholkens BA. Contribution of kinins to the cardiovascular actions of angiotensinconverting enzyme inhibitors. Pharmacol Rev 1995; 47: 25–49. Silva J-A Jr., Araujo R, Baltatu O, et al. Reduced cardiac hypertrophy and altered blood pressure control in transgenic rats with the human tissue kallikrein gene. FASEB J 2000; 14: 1858–60. Emanueli C, Maestri R, Corradi D, et al. Dilated and failing cardiomyopathy in bradykinin B(2) receptor knockout mice. Circulation 1999; 100: 2305–07. Murphey LJ, Gainer JV, Vaughan DE, Brown NJ. Angiotensinconverting enzyme insertion/deletion polymorphism modulates the human in vivo metabolism of bradykinian. Circulation 2000; 102: 829–32. Prasad A, Husain S, Schenke W, Mincemoyer R, Epstein N, Quyyumi AA. Contribution of bradykinin receptor dysfunction to abnormal coronary vasomotion in humans. J Am Coll Cardiol 2000; 36: 1467–73. Yang XP, Liu YH, Mehta D, et al. Diminished cardioprotective response to inhibition of angiotensin-converting enzyme and angiotensin II type 1 receptor in B(2) kinin receptor gene knockout mice. Circ Res 2001; 88: 1072–79. Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ. Effect of bradykinin-receptor blockade on the response to angiotensinconverting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med 1998; 339: 1285–92. Marcic BM, Erdos EG. Protein kinase C and phosphatase inhibitors block the ability of angiotensin I-converting enzyme inhibitors to resensitize the receptor to bradykinin without altering the primary effects of bradykinin. J Pharmacol Exp Ther 2000; 294: 605–12. Benzing T, Fleming I, Blaukat A, Muller-Esterl W, Busse R. Angiotensin-converting enzyme inhibitor ramiprilat interferes with the sequestration of the B2 kinin receptor within the plasma membrane of native endothelial cells. Circulation 1999; 99: 2034–40.
Darwin the philosopher? Recently The Philosophers Magazine ran a poll to see what visitors to its website would choose as “the greatest works in the western philosophical tradition” for an imaginary UN library, so cash-strapped that it could allow only five philosophy books. The results1 were largely what philosophers might have predicted: Plato’s Republic came top, Kant’s Critique of Pure Reason second, closely followed by Aristotle (twice), Descartes, Wittgenstein, and Hume. But what surprised the editors was that Darwin’s Origin of Species came third. Darwin was not, in the modern understanding of the term, a philosopher at all. Academic philosophy is a purely rational inquiry, and research that involves observation and experiment is, to that extent, not philosophical. But Darwin was a meticulous observer and experimenter, bent on understanding the causal mechanisms by which living things had come to be the way they were. He was obviously a scientist. Why, then, did so many philosophers place him among their number? One possibility is that although there is a radical difference between philosophical and empirical investigation, it does not follow that there is a gulf between philosophy and science. Science necessarily involves empirical work, but there is more to it than that. As Thomas Kuhn pointed out, when sciences are in their infancy, and during scientific revolutions, philosophical thinking becomes an integral part of the work of science. 1118
During periods of what Kuhn calls normal science—the sort of science most scientists are engaged in most of the time—scientific inquiries, although often difficult and demanding, are conducted against a theoretical background that defines both the questions asked and the kind of answer expected. Crick and Watson, for instance, made a monumental discovery; but the problem they were investigating presupposed the well-established framework of molecular theory. The trouble for normal science begins when it starts to produce anomalous results that gradually undermine the background theory itself. When this happens, what is needed is not just more empirical information, but a theoretical breakthrough that will make sense of the information there already is. It is this work that may, to a greater or lesser extent, involve philosophical reasoning. Such an accumulation of anomalies was the problem faced by Darwin and his scientific contemporaries. They knew that traditional religious ideas about the origins of life on earth were irreconcilable with the accumulating evidence, but had only hazy ideas of what to put in their place. Darwin’s vast empirical knowledge of course influenced his thinking, but his crucial breakthrough was not a critical empirical discovery. The core of his theory—the idea of evolution by natural selection—was a matter of recognising the logical implications of simple facts that everyone knew: that offspring resembled parents, and that more offspring were born than could possibly survive. Still it cannot be said that Darwin’s work was substantially philosophical in the way that Aristotle’s, or Newton’s, or Einstein’s was. So it seems more likely that what accounts for the magazine readers’ choice is the converse of the involvement of philosophy in parts of science: the fact that scientific advance can influence the work of philosophy, and that Darwin’s work has had more impact on philosophical thinking than that of any other scientist. The reason for this impact is the one that made Darwin’s theory so shocking in its own time. Until Darwin, the only possible explanation of complex design in the universe had seemed to be that mind, or rather Mind, must underlie everything else. After Darwin, it became possible to understand how order and complexity could have arisen by purely natural means. This huge development has made no difference to the nature of philosophy as an inquiry, but it has radically affected the kinds of question philosophers ask, and transformed the conduct of philosophy of mind, ethics, metaphysics, cosmology, and even epistemology. I still find it odd that Darwin appeared on this list of philosophers. Nevertheless, if there were any doubt about his inclusion in the science sections of this remarkably parsimonious UN library, I would stretch the theoretical point and give him one of the philosophical places. Philosopher or not, he made one of the greatest contributions ever towards solving problems that have preoccupied philosophers since the subject began. Janet Radcliffe Richards Centre for Bioethics and Philosophy of Medicine, University College London, London N19 2UA, UK (e-mail: [email protected] 1
Chandler J. Top of the forms. The Philosophers Magazine, 2001, issue 16: 11–12 (www.philosophers.co.uk/poll.htm, accessed on Oct 2, 2001)
THE LANCET • Vol 358 • October 6, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
expressed in calcified arterial lesions both in atherosclerosis and in the vascular disease associated with chronic renal failure.18,19 Among these are bone morphogenetic protein 2, osteocalcin, and bone sialoprotein. Recently Ahmed and colleagues9 used immunohistochemistry to demonstrate expression of the bone-matrix protein osteopontin in arterial tissues obtained from patients with CUA. Osteopontin expression was limited to vessels that contained calcium deposits but was absent in uncalcified vessels from the same individuals. Although a causative role for osteopontin cannot be inferred, the results suggest that selected bone-related proteins are involved either primarily or secondarily in the process of vascular calcification in renal failure. In this regard, the finding that warfarin affects the vascular calcification in laboratory animals may have direct clinical relevance.20 Mice with inactivating mutations in both alleles of the gene encoding matrix GLA protein (MGP) inappropriately calcify various cartilages, including the epiphyseal growth plate, leading to skeletal deformities and osteoporosis.21 More notably, the animals die several months after birth from haemorrhage due to the rupture of extensively calcified arteries. Such findings indicate that MGP has a fundamental physiological role as an inhibitor of calcification in vascular tissue. Pharmacological agents, such as warfarin, that inhibit MGP synthesis may, therefore, disrupt an important mechanism for preserving vascular integrity. Although not addressed specifically in the study by Mazhar and colleagues, seven of 19 (37%) of cases of CUA but only one of 54 (2%) of controls had been treated with warfarin.8 It may be prudent therefore to reassess the safety and suitability of warfarin as a means of preventing thrombosis in arteriovenous fistulas and grafts in patients undergoing haemodialysis to ensure that it does not aggravate the vascular calcification to which these patients are prone. What recent work has also indicated is that, apart from the risks traditionally associated with disturbances in mineral metabolism due to chronic renal failure, localised changes in the tissuespecific expression or function of various bone-related proteins such as osteopontin and MGP may also contribute to the development of CUA. William G Goodman Division of Nephrology, Department of Medicine, UCLA School of Medicine, Los Angeles, CA 9005, USA (e-mail: [email protected]) 1
2
3
4
5 6 7
8
Gipstein RM, Coburn JW, Adams JA, et al. Calciphylaxis in man: a syndrome of tissue necrosis and vascular calcification in 11 patients with chronic renal failure. Arch Intern Med 1976; 136: 1273–80. Conn J Jr, Krumlovsky FA, del Greco F, Simon NM. Calciphylaxis: etiology of progressive vascular calcification and gangrene? Ann Surg 1973; 177: 206–10. Androuge H, Frazier M, Zeluff B, Suki WN. Systemic calciphylaxis: successful treatment with parathyroidectomy. J Urol 1983; 129: 362–63. Fox R, Banowsky LH, Cruz AB, Jr. Post-renal transplant calciphylaxis: successful treatment with parathyroidectomy. J Urol 1983; 129: 362–63. Llach F. The evolving pattern of calciphylaxis: therapeutic considerations. Nephrol Dial Transplant 2001; 16: 448–51. Selye H, Gabbiani G, Strebel R. Sensitization to calciphylaxis by endogenous parathyroid hormone. Endocrinology 1962; 50: 554-58. Ruggian J, Maesaka J, Fishbane S. Proximal calciphylaxis in four insulin-requiring diabetic hemodialysis patients. Am J Kidney Dis 1996; 28: 409–14. Mazhar AR, Johnson RJ, Gillen D, et al. Risk factors and mortality associated with calciphylaxis in end-stage renal disease. Kidney Int 2001; 60: 324–32.
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Ahmed S, O’Neill KD, Hood AF, Evan AP, Moe SM. Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells. Am J Kidney Dis 2001; 37: 1267–76. Marchais SJ, Metivier F, Guerin AP, London GM. Association of hyperphosphataemia with haemodynamic disturbances in end-stage renal disease. Nephrol Dial Transplant 1999; 14: 2178–83. Guérin AP, London GM, Marchais SJ, Metivier F. Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 2000; 15: 1014–21. Goodman WG, Goldin J, Kuizon BD, et al. Coronary artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000; 342: 1478–83. Mawad HW, Sawaya BP, Sarin R, Malluche HH. Calcific uremic arteriolopathy in association with low turnover uremic bone disease. Clin Nephrol 1999; 52: 160–66. Salusky IB, Ramirez JA, Oppenheim WL, Gales B, Segre GV, Goodman WG. Biochemical markers of renal osteodystrophy in pediatric patients undergoing CAPD/CCPD. Kidney Int 1994; 45: 253–58. Hutchison AJ, Whitehouse RW, Freemont AJ, Adams JE, Mawer EB, Gokal R. Histological, radiological, and biochemical features of the adynamic bone lesion in continuous ambulatory peritoneal dialysis patients. Am J Nephrol 1994; 14: 19–29. Sherrard DJ, Hercz G, Pei Y, Segre G. The aplastic form of renal osteodystrophy. Nephrol Dial Transplant1996; 11 (suppl 3): 29–31. Zacharias JM, Fontaine B, Fine A. Calcium use increases risk of calciphylaxis: a case-control study. Perit Dial Int 1999; 19: 248–52. Shanahan CM, Proudfoot D, Tyson KL, Cary NR, Edmonds M, Weissberg PL. Expression of mineralisation-regulating proteins in association with human vascular calcification. Z Kardiol 2000; 89 (suppl 2): 63–68. Shanahan CM, Cary NR, Salisbury JR, Proudfoot D, Weissberg PL, Edmonds ME. Medial localization of mineralization-regulating proteins in association with Monckeberg’s sclerosis: evidence for smooth muscle cell-mediated vascular calcification. Circulation 1999; 100: 2168–76. Shanahan CM, Proudfoot D, Farzaneh-Far A, Weissberg PL. The role of Gla proteins in vascular calcification. Crit Rev Eukaryot Gene Expr 1998; 8: 357–75. Luo G, Ducy P, McKee MD, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 1997; 386: 78–81.
Bradykinin in protection against leftventricular hypertrophy See page 1155
Left-ventricular hypertrophy (LVH) substantially increases risk of sudden death and other cardiovascular complications even after adjustment for other known risk factors.1 On the basis of the pressor and remodelling effects of antiotensin II, the renin-angiotensin system is widely thought to play an important part in the development of LVH. The efficacy of angiotensinconverting-enzyme (ACE) inhibitors in lessening progressive left-ventricular (LV) remodelling and rates of sudden death in patients with left-ventricular dysfunction further underscores the potential importance this system. Understanding how the reninangiotensin system modulates the development of LVH is thus of clinical importance. The major components of the renin-angiotensin system are illustrated in the figure. ACE not only generates the biologically active peptide angiotensin II but also degrades bradykinin. Kinetic studies have shown that bradykinin is the preferred ACE substrate.2 Of the two angiotensin II receptors that have been identified, the type 1 (AT1) receptor mediates the classic pressor effects of angiotensin II, whereas the type 2 (AT2) receptor mediates hypotensive effects. The increasing number of human polymorphisms that have been identified provides new opportunities to define genetic contributions to common yet complex diseases such as LVH. Polymorphisms of all four of the
THE LANCET • Vol 358 • October 6, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
Renin-angiotensin system Angiotensinogen Renin
Degradation products Angiotensin I
Chymase
ACE
Angiotensin II
Bradykinin
ACE
AT1R
B2BKR
AT2R Cell
Enzymes are indicated in italics. Abbreviations used: AT1R=AT1 receptor; AT2R=AT2 receptor; B2BKR=B2 bradykinin receptor
genes for the renin-angiotensin system have been linked to the development of LVH.3 These polymorphisms are ACE deletion (D) or insertion (I), AT1 receptor A1166C, AT2 receptor G1675A, and angiotensinogen M235T. Several additional angiotensinogen gene polymorphisms (G-6A, T31C, and T174M) are in linkage dysequilibrium with M235T and have also been implicated.2 The best studied of these polymorphisms is the ACE D or I polymorphism that influences ACE concentrations and activity. The D allele is linked to increased ACE activity in a gene dose-dependent manner, and the DD genotype has been repeatedly (though not universally) associated with increased risk of LVH. How might the D allele increase the risk of developing LVH? Two answers have been proposed: increased generation of angiotensin II or increased degradation of bradykinin. Attempts to resolve this question have been confounded, however, by the clinical heterogeneity of patients with LVH. In normotensive individuals undergoing vigorous physical training, LV mass has been shown to increase predictably, so these people form a suitable population in which to study the effect of the ACE insertion/deletion polymorphism on LV growth. In a prospective study of healthy normotensive male army recruits about to start a physical training programme, Myerson and colleagues4 showed that the increase in LV growth during training correlated with the ACE insertion/deletion genotype—being greatest in men with the D/D genotype, intermediate in men with the D/I genotype, and lowest in men with the I/I genotype. They then made the critical observation that prophylactic treatment with the AT1-receptor antagonist losartan had no impact on LV growth, which suggested that the effect of the ACE insertion/deletion polymorphism on LV mass was most probably due to its effect on cardiac bradykinin concentrations. In today’s Lancet, David Brull and colleagues report on an extension of Myerson and colleagues’ study. They examined the effect of the +9/–9 B2 bradykinin receptor polymorphism. The B2 bradykinin receptor is stimulated by bradykinin, and the –9 allele has previously been shown to result in more B2 bradykinin-receptor mRNA than has the +9 allele.5 Brull and colleagues found that
THE LANCET • Vol 358 • October 6, 2001
LV growth during training correlated with gene dose of the +9 allele for the B2 bradykinin receptor, and that the ACE and bradykinin- receptor genotypes interacted additively. Thus individuals with the greatest increase in LV mass had the highest concentrations of ACE (D/D genotype) and the lowest concentrations of B2 bradykinin receptor (+9/+9 genotype). These results strongly support an important role for bradykinin in the ACE-mediated effect on LVH. All components of a functional bradykinin system are expressed in the heart, and bradykinin clearly mediates important cardiovascular effects, such as increased vascular permeability, enhanced myocardial glucose uptake, negative inotropism, and inhibition of myocardial growth.2,6 Many, but not all, of these effects are secondary to its ability to potently stimulate generation of autacoids, such as nitric oxide and prostaglandins. Bradykinin has been shown to play an integral part in protecting the ischaemic myocardium. Furthermore, transgenic rats overexpressing tissue kallikrein (a kinin-generating enzyme) develop less cardiac hypertrophy and fibrosis than do wild-type rats.7 Conversely, genetically ablating B2 bradykinin receptors results in enhanced salt-induced hypertension and hypertrophic cardiomyopathy.8 There is also considerable evidence supporting interactions between bradykinin and the reninangiotensin system. The ACE D allele has been shown to have a significant effect on the in-vivo degradation of bradykinin in human beings;9 and epicardial vasodilatory responses to intracoronary bradykinin administration were depressed in patients with the ACE D/D genotype.10 The cardioprotective effect of ACE inhibitors was lost in B2 bradykinin-receptor knock-out mice,11 and a B2 bradykinin-receptor antagonist significantly attenuated the antihypertensive of effect of ACE inhibitors in human beings.12 Additionally, ACE inhibitors have been shown to mediate cross-talk between membrane-bound ACE and B2 bradykinin receptors, which resulted in enhanced bradykinin activity due to prevention of receptor desensitisation.13,14 It now seems probable that bradykinin is an important participant in the cardiac effects of the renin-angiotensin system; and novel pharmaceutical approaches to further increase cardiac bradykinin concentrations may be clinically beneficial. Additional studies, however, need to clarify whether the processes found in exercise-induced LV growth in normotensive people also occur in pathological LVH. It is important also to recognise that the ACE and B2 bradykinin-receptor polymorphisms account for only a fraction of the total variability in the expression of LVH. A complete understanding of LVH variability is certain to be extremely complex, involving multiple gene interactions as well as gene-environment interactions. Brull and colleagues’ findings are, however, an important first step in the unravelling of the relation between ACE activity, bradykinin, and LVH. Bruce Zuraw Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA 92037, USA (e-mail: [email protected])
1
2 3
Lorell BH, Carabello BA. Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation 2000; 102: 470–79. Dell’Itlalia, LJ, Oparil S. Bradykinin in the heart: friend or foe? Circulation 1999; 100: 2305–07. Wang J-G, Staessen JA. Genetic polymorphisms in the renin-
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COMMENTARY
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angiotensin system: relevance for susceptibility to cardiovascular disease. Eur J Pharmacol 2000; 410: 289–302. Myerson SG, Montgomery HE, Whittingham M, et al. Left ventricular hypertrophy with exercise and ACE gene insertion/deletion polymorphism: a randomized controlled trial with losartan. Circulation 2001; 103: 226–30. Lung CC, Chan EK, Zuraw BL. Analysis of an exon 1 polymorphism of the B2 bradykinin receptor gene and its transcript in normal subjects and patients with C1 inhibitor deficiency. J Allergy Clin Immunol 1997; 99: 134–46. Linz W, Wiemer G, Gohlke P, Unger T, Scholkens BA. Contribution of kinins to the cardiovascular actions of angiotensinconverting enzyme inhibitors. Pharmacol Rev 1995; 47: 25–49. Silva J-A Jr., Araujo R, Baltatu O, et al. Reduced cardiac hypertrophy and altered blood pressure control in transgenic rats with the human tissue kallikrein gene. FASEB J 2000; 14: 1858–60. Emanueli C, Maestri R, Corradi D, et al. Dilated and failing cardiomyopathy in bradykinin B(2) receptor knockout mice. Circulation 1999; 100: 2305–07. Murphey LJ, Gainer JV, Vaughan DE, Brown NJ. Angiotensinconverting enzyme insertion/deletion polymorphism modulates the human in vivo metabolism of bradykinian. Circulation 2000; 102: 829–32. Prasad A, Husain S, Schenke W, Mincemoyer R, Epstein N, Quyyumi AA. Contribution of bradykinin receptor dysfunction to abnormal coronary vasomotion in humans. J Am Coll Cardiol 2000; 36: 1467–73. Yang XP, Liu YH, Mehta D, et al. Diminished cardioprotective response to inhibition of angiotensin-converting enzyme and angiotensin II type 1 receptor in B(2) kinin receptor gene knockout mice. Circ Res 2001; 88: 1072–79. Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ. Effect of bradykinin-receptor blockade on the response to angiotensinconverting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med 1998; 339: 1285–92. Marcic BM, Erdos EG. Protein kinase C and phosphatase inhibitors block the ability of angiotensin I-converting enzyme inhibitors to resensitize the receptor to bradykinin without altering the primary effects of bradykinin. J Pharmacol Exp Ther 2000; 294: 605–12. Benzing T, Fleming I, Blaukat A, Muller-Esterl W, Busse R. Angiotensin-converting enzyme inhibitor ramiprilat interferes with the sequestration of the B2 kinin receptor within the plasma membrane of native endothelial cells. Circulation 1999; 99: 2034–40.
Darwin the philosopher? Recently The Philosophers Magazine ran a poll to see what visitors to its website would choose as “the greatest works in the western philosophical tradition” for an imaginary UN library, so cash-strapped that it could allow only five philosophy books. The results1 were largely what philosophers might have predicted: Plato’s Republic came top, Kant’s Critique of Pure Reason second, closely followed by Aristotle (twice), Descartes, Wittgenstein, and Hume. But what surprised the editors was that Darwin’s Origin of Species came third. Darwin was not, in the modern understanding of the term, a philosopher at all. Academic philosophy is a purely rational inquiry, and research that involves observation and experiment is, to that extent, not philosophical. But Darwin was a meticulous observer and experimenter, bent on understanding the causal mechanisms by which living things had come to be the way they were. He was obviously a scientist. Why, then, did so many philosophers place him among their number? One possibility is that although there is a radical difference between philosophical and empirical investigation, it does not follow that there is a gulf between philosophy and science. Science necessarily involves empirical work, but there is more to it than that. As Thomas Kuhn pointed out, when sciences are in their infancy, and during scientific revolutions, philosophical thinking becomes an integral part of the work of science. 1118
During periods of what Kuhn calls normal science—the sort of science most scientists are engaged in most of the time—scientific inquiries, although often difficult and demanding, are conducted against a theoretical background that defines both the questions asked and the kind of answer expected. Crick and Watson, for instance, made a monumental discovery; but the problem they were investigating presupposed the well-established framework of molecular theory. The trouble for normal science begins when it starts to produce anomalous results that gradually undermine the background theory itself. When this happens, what is needed is not just more empirical information, but a theoretical breakthrough that will make sense of the information there already is. It is this work that may, to a greater or lesser extent, involve philosophical reasoning. Such an accumulation of anomalies was the problem faced by Darwin and his scientific contemporaries. They knew that traditional religious ideas about the origins of life on earth were irreconcilable with the accumulating evidence, but had only hazy ideas of what to put in their place. Darwin’s vast empirical knowledge of course influenced his thinking, but his crucial breakthrough was not a critical empirical discovery. The core of his theory—the idea of evolution by natural selection—was a matter of recognising the logical implications of simple facts that everyone knew: that offspring resembled parents, and that more offspring were born than could possibly survive. Still it cannot be said that Darwin’s work was substantially philosophical in the way that Aristotle’s, or Newton’s, or Einstein’s was. So it seems more likely that what accounts for the magazine readers’ choice is the converse of the involvement of philosophy in parts of science: the fact that scientific advance can influence the work of philosophy, and that Darwin’s work has had more impact on philosophical thinking than that of any other scientist. The reason for this impact is the one that made Darwin’s theory so shocking in its own time. Until Darwin, the only possible explanation of complex design in the universe had seemed to be that mind, or rather Mind, must underlie everything else. After Darwin, it became possible to understand how order and complexity could have arisen by purely natural means. This huge development has made no difference to the nature of philosophy as an inquiry, but it has radically affected the kinds of question philosophers ask, and transformed the conduct of philosophy of mind, ethics, metaphysics, cosmology, and even epistemology. I still find it odd that Darwin appeared on this list of philosophers. Nevertheless, if there were any doubt about his inclusion in the science sections of this remarkably parsimonious UN library, I would stretch the theoretical point and give him one of the philosophical places. Philosopher or not, he made one of the greatest contributions ever towards solving problems that have preoccupied philosophers since the subject began. Janet Radcliffe Richards Centre for Bioethics and Philosophy of Medicine, University College London, London N19 2UA, UK (e-mail: [email protected] 1
Chandler J. Top of the forms. The Philosophers Magazine, 2001, issue 16: 11–12 (www.philosophers.co.uk/poll.htm, accessed on Oct 2, 2001)
THE LANCET • Vol 358 • October 6, 2001
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