Heart Failure Reviews

, Volume 17, Issue 4–5, pp 683–691 | Cite as

Role of ACE2 in diastolic and systolic heart failure

  • Wang Wang
  • Sreedhar Bodiga
  • Subhash K. Das
  • Jennifer Lo
  • Vaibhav Patel
  • Gavin Y. Oudit
Article

Abstract

A novel angiotensin-converting enzyme (ACE) homolog, named ACE2, is a monocarboxypeptidase which metabolizes several peptides. ACE2 degrades Angiotensin (Ang) II, a peptide with vasoconstrictive/proliferative effects, to generate Ang-(1-7), which acting through its receptor Mas exerts vasodilatory/anti-proliferative actions. In addition, as ACE2 is a multifunctional enzyme and its actions on other vasoactive peptides can also contribute to its vasoactive effects including the apelin-13 and apelin-17 peptides. The discovery of ACE2 corroborates the establishment of two counter-regulatory arms within the renin-angiotensin system. The first one is formed by the classical pathway involving the ACE-Ang II-AT1 receptor axis and the second arm is constituted by the ACE2-Ang 1-7/Mas receptor axis. Loss of ACE2 enhances the adverse pathological remodeling susceptibility to pressure-overload and myocardial infarction. ACE2 is also a negative regulator of Ang II-induced myocardial hypertrophy, fibrosis, and diastolic dysfunction. The ACE2-Ang 1-7/Mas axis may represent new possibilities for developing novel therapeutic strategies for the treatment of hypertension and cardiovascular diseases. In this review, we will summarize the biochemical and pathophysiological aspects of ACE2 with a focus on its role in diastolic and systolic heart failure.

Keywords

Angiotensin-converting enzyme 2 Angiotensin II Angiotensin 1-7 Diastolic dysfunction Hypertension Heart failure 

Notes

Acknowledgments

GYO is a Clinician-Investigator of the Alberta Innovates—Health Solutions and the Distinguish Clinician Scientist of the Heart and Stroke Foundation of Canada and Canadian Institutes of Health Research. WW is supported by a Mazankowski Alberta Heart Institute Studentship and SB is a Postdoctoral Fellow of Alberta Innovates—Health Solutions.

References

  1. 1.
    Zaman MA, Oparil S, Calhoun DA (2002) Drugs targeting the renin-angiotensin-aldosterone system. Nat Rev Drug Discov 1:621–636PubMedCrossRefGoogle Scholar
  2. 2.
    Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ (2000) A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 275:33238–33243PubMedCrossRefGoogle Scholar
  3. 3.
    Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S (2000) A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res 87:E1–E9PubMedGoogle Scholar
  4. 4.
    Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, Oliveira-dos-Santos AJ, da Costa J, Zhang L, Pei Y, Scholey J, Ferrario CM, Manoukian AS, Chappell MC, Backx PH, Yagil Y, Penninger JM (2002) Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 417:822–828PubMedCrossRefGoogle Scholar
  5. 5.
    Oudit GY, Kassiri Z, Patel MP, Chappell M, Butany J, Backx PH, Tsushima RG, Scholey JW, Khokha R, Penninger JM (2007) Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice. Cardiovasc Res 75:29–39PubMedCrossRefGoogle Scholar
  6. 6.
    Zhong J, Basu R, Guo D, Chow FL, Byrns S, Schuster M, Loibner H, Wang XH, Penninger JM, Kassiri Z, Oudit GY (2010) Angiotensin converting enzyme 2 suppresses pathological hypertrophy, myocardial fibrosis and cardiac dysfunction. Circulation 122:717–728PubMedCrossRefGoogle Scholar
  7. 7.
    Bodiga S, Zhong JC, Wang W, Basu R, Lo J, Liu GC, Guo D, Holland SM, Scholey JW, Penninger JM, Kassiri Z, Oudit GY (2011) Enhanced susceptibility to biomechanical stress in ACE2 null mice is prevented by loss of the p47phox NADPH oxidase subunit. Cardiovasc Res (in press)Google Scholar
  8. 8.
    Lovren F, Pan Y, Quan A, Teoh H, Wang G, Shukla PC, Levitt KS, Oudit GY, Al-Omran M, Stewart DJ, Slutsky AS, Peterson MD, Backx PH, Penninger JM, Verma S (2008) Angiotensin converting enzyme-2 confers endothelial protection and attenuates atherosclerosis. Am J Physiol Heart Circ Physiol 295:H1377–H1384PubMedCrossRefGoogle Scholar
  9. 9.
    Rentzsch B, Todiras M, Iliescu R, Popova E, Campos LA, Oliveira ML, Baltatu OC, Santos RA, Bader M (2008) Transgenic angiotensin-converting enzyme 2 overexpression in vessels of SHRSP rats reduces blood pressure and improves endothelial function. Hypertension 52:967–973PubMedCrossRefGoogle Scholar
  10. 10.
    Wysocki J, Ye M, Rodriguez E, González-Pacheco FR, Barrios C, Evora K, Schuster M, Loibner H, Brosnihan KB, Ferrario CM, Penninger JM, Batlle D (2009) Targeting the degradation of angiotensin II with recombinant angiotensin-converting enzyme 2: prevention of angiotensin II-dependent hypertension. Hypertension 55:90–98PubMedCrossRefGoogle Scholar
  11. 11.
    Oudit GY, Herzenberg AM, Kassiri Z, Wong D, Reich H, Khokha R, Crackower MA, Backx PH, Penninger JM, Scholey JW (2006) Loss of angiotensin-converting enzyme-2 leads to the late development of angiotensin II-dependent glomerulosclerosis. Am J Pathol 168:1808–1820PubMedCrossRefGoogle Scholar
  12. 12.
    Oudit GY, Liu GC, Zhong J, Basu R, Chow FL, Zhou J, Loibner H, Janzek E, Schuster M, Penninger JM, Herzenberg AM, Kassiri Z, Scholey JW (2010) Human recombinant ACE2 reduces the progression of diabetic nephropathy. Diabetes 59:529–538PubMedCrossRefGoogle Scholar
  13. 13.
    Zhong J, Guo D, Chen CB, Wang W, Schuster M, Loibner H, Penninger JM, Scholey JW, Kassiri Z, Oudit GY (2011) Prevention of angiotensin II-mediated renal oxidative stress, inflammation, and fibrosis by angiotensin-converting enzyme 2. Hypertension 57:314–322PubMedCrossRefGoogle Scholar
  14. 14.
    Ishiyama Y, Gallagher PE, Averill DB, Tallant EA, Brosnihan KB, Ferrario CM (2004) Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension 43:970–976PubMedCrossRefGoogle Scholar
  15. 15.
    Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, Diz DI, Gallagher PE (2005) Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 111:2605–2610PubMedCrossRefGoogle Scholar
  16. 16.
    Ocaranza MP, Godoy I, Jalil JE, Varas M, Collantes P, Pinto M, Roman M, Ramirez C, Copaja M, Diaz-Araya G, Castro P, Lavandero S (2006) Enalapril attenuates downregulation of Angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat. Hypertension 48:572–578PubMedCrossRefGoogle Scholar
  17. 17.
    Zhong JC, Ye JY, Jin HY, Yu X, Yu HM, Zhu DL, Gao PJ, Huang DY, Shuster M, Loibner H, Guo JM, Yu XY, Xiao BX, Gong ZH, Penninger JM, Oudit GY (2011) Telmisartan attenuates aortic hypertrophy in hypertensive rats by the modulation of ACE2 and profilin-1 expression. Regul Pept 166:90–97PubMedCrossRefGoogle Scholar
  18. 18.
    Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J, Godbout K, Parsons T, Baronas E, Hsieh F, Acton S, Patane M, Nichols A, Tummino P (2002) Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 277:14838–14843PubMedCrossRefGoogle Scholar
  19. 19.
    Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I, Heringer-Walther S, Pinheiro SV, Lopes MT, Bader M, Mendes EP, Lemos VS, Campagnole-Santos MJ, Schultheiss HP, Speth R, Walther T (2003) Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA 100:8258–8263PubMedCrossRefGoogle Scholar
  20. 20.
    Mercure C, Yogi A, Callera GE, Aranha AB, Bader M, Ferreira AJ, Santos RA, Walther T, Touyz RM, Reudelhuber TL (2008) Angiotensin(1-7) blunts hypertensive cardiac remodeling by a direct effect on the heart. Circ Res 103:1319–1326PubMedCrossRefGoogle Scholar
  21. 21.
    Turner AJ, Hiscox JA, Hooper NM (2004) ACE2: from vasopeptidase to SARS virus receptor. Trends Pharmacol Sci 25:291–294PubMedCrossRefGoogle Scholar
  22. 22.
    Guy JL, Jackson RM, Acharya KR, Sturrock ED, Hooper NM, Turner AJ (2003) Angiotensin-converting enzyme-2 (ACE2): comparative modeling of the active site, specificity requirements, and chloride dependence. Biochemistry 42:13185–13192PubMedCrossRefGoogle Scholar
  23. 23.
    Epelman S, Shrestha K, Troughton RW, Francis GS, Sen S, Klein AL, Tang WH (2009) Soluble angiotensin-converting enzyme 2 in human heart failure: relation with myocardial function and clinical outcomes. J Card Fail 15:565–571PubMedCrossRefGoogle Scholar
  24. 24.
    Lambert DW, Yarski M, Warner FJ, Thornhill P, Parkin ET, Smith AI, Hooper NM, Turner AJ (2005) Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). J Biol Chem 80:30113–301139CrossRefGoogle Scholar
  25. 25.
    Garabelli PJ, Modrall JG, Penninger JM, Ferrario CM, Chappell MC (2008) Distinct roles for angiotensin-converting enzyme 2 and carboxypeptidase A in the processing of angiotensins within the murine heart. Exp Physiol 93:613–621PubMedCrossRefGoogle Scholar
  26. 26.
    Kassiri Z, Zhong J, Guo D, Basu R, Wang X, Liu PP, Scholey JW, Penninger JM, Oudit GY (2009) Loss of angiotensin-converting enzyme 2 accelerates maladaptive left ventricular remodeling in response to myocardial infarction. Circ Heart Fail 2:446–455PubMedCrossRefGoogle Scholar
  27. 27.
    Santos RA, Ferreira AJ, Pinheiro SV, Sampaio WO, Touyz R, Campagnole-Santos MJ (2005) Angiotensin-(1-7) and its receptor as a potential targets for new cardiovascular drugs. Expert Opin Investig Drugs 14:1019–1031PubMedCrossRefGoogle Scholar
  28. 28.
    Lee DK, Cheng R, Nguyen T, Fan T, Kariyawasam AP, Liu Y, Osmond DH, George SR, O’Dowd BF (2000) Characterization of apelin, the ligand for the APJ receptor. J Neurochem 74:34–41PubMedCrossRefGoogle Scholar
  29. 29.
    Pitkin SL, Maguire JJ, Bonner TI, Davenport AP (2010) International union of basic and clinical pharmacology. LXXIV. Apelin receptor nomenclature, distribution, pharmacology, and function. Pharmacol Rev 62:331–342PubMedCrossRefGoogle Scholar
  30. 30.
    Gallagher PE, Ferrario CM, Tallant EA (2008) Regulation of ACE2 in cardiac myocytes and fibroblasts. Am J Physiol Heart Circ Physiol 295:H2373–H2379PubMedCrossRefGoogle Scholar
  31. 31.
    Goulter AB, Goddard MJ, Allen JC, Clark KL (2004) ACE2 gene expression is up-regulated in the human failing heart. BMC Med 2:19PubMedCrossRefGoogle Scholar
  32. 32.
    Burrell LM, Risvanis J, Kubota E, Dean RG, MacDonald PS, Lu S, Tikellis C, Grant SL, Lew RA, Smith AI, Cooper ME, Johnston CI (2005) Myocardial infarction increases ACE2 expression in rat and humans. Eur Heart J 26:369–375PubMedCrossRefGoogle Scholar
  33. 33.
    Gurley SB, Allred A, Le TH, Griffiths R, Mao L, Philip N, Haystead TA, Donoghue M, Breitbart RE, Acton SL, Rockman HA, Coffman TM (2006) Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice. J Clin Invest 116:2218–2225PubMedCrossRefGoogle Scholar
  34. 34.
    Yamamoto K, Ohishi M, Katsuya T, Ito N, Ikushima M, Kaibe M, Tatara Y, Shiota A, Sugano S, Takeda S, Rakugi H, Ogihara T (2006) Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II. Hypertension 47:718–726PubMedCrossRefGoogle Scholar
  35. 35.
    Lieb W, Graf J, Götz A, König IR, Mayer B, Fischer M, Stritzke J, Hengstenberg C, Holmer SR, Döring A, Löwel H, Schunkert H, Erdmann J (2006) Association of angiotensin-converting enzyme 2 (ACE2) gene polymorphisms with parameters of left ventricular hypertrophy in men. Results of the MONICA Augsburg echocardiographic substudy. J Mol Med 84:88–96PubMedCrossRefGoogle Scholar
  36. 36.
    Yang W, Huang W, Su S, Li B, Zhao W, Chen S, Gu D (2006) Association study of ACE2 (angiotensin I-converting enzyme 2) gene polymorphisms with coronary heart disease and myocardial infarction in a Chinese Han population. Clin Sci (Lond) 111:333–340CrossRefGoogle Scholar
  37. 37.
    Zhong J, Yan Z, Liu D, Ni Y, Zhao Z, Zhu S, Tepel M, Zhu Z (2006) Association of angiotensin-converting enzyme 2 gene A/G polymorphism and elevated blood pressure in Chinese patients with metabolic syndrome. J Lab Clin Med 147:91–95PubMedCrossRefGoogle Scholar
  38. 38.
    Zhao YX, Yin HQ, Yu QT, Qiao Y, Dai HY, Zhang MX, Zhang L, Liu YF, Wang LC, de Liu S, Deng BP, Zhang YH, Pan CM, Song HD, Qu X, Jiang H, Liu CX, Lu XT, Liu B, Gao F, Dong B (2010) ACE2 overexpression ameliorates left ventricular remodeling and dysfunction in a rat model of myocardial infarction. Hum Gene Ther 21:1545–1554PubMedCrossRefGoogle Scholar
  39. 39.
    Grobe JL, Der Sarkissian S, Stewart JM, Meszaros JG, Raizada MK, Katovich MJ (2007) ACE2 overexpression inhibits hypoxia-induced collagen production by cardiac fibroblasts. Clin Sci (Lond) 113:357–364CrossRefGoogle Scholar
  40. 40.
    Wang Y, Moreira Mda C, Heringer-Walther S, Ebermann L, Schultheiss HP, Wessel N, Siems WE, Walther T (2010) Plasma ACE2 activity is an independent prognostic marker in Chagas’ disease and equally potent as BNP. J Card Fail 16:157–163PubMedCrossRefGoogle Scholar
  41. 41.
    Xie X, Chen J, Wang X, Zhang F, Liu Y (2006) Age- and gender-related difference of ACE2 expression in rat lung. Life Sci 78:2166–2171PubMedCrossRefGoogle Scholar
  42. 42.
    Jugdutt BI (2010) Aging and heart failure: changing demographics and implications for therapy in the elderly. Heart Fail Rev 15:401–405PubMedCrossRefGoogle Scholar
  43. 43.
    Jelani A, Jugdutt BI (2010) STEMI and heart failure in the elderly: role of adverse remodeling. Heart Fail Rev 15:513–521PubMedCrossRefGoogle Scholar
  44. 44.
    Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, Gong Y, Liu PP (2006) Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 355:260–269PubMedCrossRefGoogle Scholar
  45. 45.
    Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM (2006) Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 355:251–259PubMedCrossRefGoogle Scholar
  46. 46.
    Zile MR, Brutsaert DL (2002) New concepts in diastolic dysfunction and diastolic heart failure: Part II: causal mechanisms and treatment. Circulation 105:1503–1508PubMedCrossRefGoogle Scholar
  47. 47.
    Iwata M, Cowling RT, Gurantz D, Moore C, Zhang S, Yuan JX, Greenberg BH (2005) Angiotensin-(1-7) binds to specific receptors on cardiac fibroblasts to initiate antifibrotic and antitrophic effects. Am J Physiol Heart Circ Physiol 289:H2356–H2363PubMedCrossRefGoogle Scholar
  48. 48.
    Weber KT, Brilla CG (1991) Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation 83:1849–1865PubMedGoogle Scholar
  49. 49.
    Huentelman MJ, Grobe JL, Vazquez J, Stewart JM, Mecca AP, Katovich MJ, Ferrario CM, Raizada MK (2005) Protection from angiotensin II-induced cardiac hypertrophy and fibrosis by systemic lentiviral delivery of ACE2 in rats. Exp Physiol 90:783–790PubMedCrossRefGoogle Scholar
  50. 50.
    Wei CC, Hase N, Inoue Y, Bradley EW, Yahiro E, Li M, Naqvi N, Powell PC, Shi K, Takahashi Y, Saku K, Urata H, Dell’italia LJ, Husain A (2010) Mast cell chymase limits the cardiac efficacy of Ang I-converting enzyme inhibitor therapy in rodents. J Clin Invest 120:1229–1239PubMedCrossRefGoogle Scholar
  51. 51.
    Carretero OA, Oparil S (2000) Essential hypertension. Part I: definition and etiology. Circulation 101:329–335PubMedGoogle Scholar
  52. 52.
    Stoll M, Jacob HJ (2001) Genetic rat models of hypertension: relationship to human hypertension. Curr Hypertens Rep 3:157–164PubMedCrossRefGoogle Scholar
  53. 53.
    Oudit GY, Crackower MA, Backx PH, Penninger JM (2003) The role of ACE2 in cardiovascular physiology. Trends Cardiovasc Med 13:93–101PubMedCrossRefGoogle Scholar
  54. 54.
    Yamazato M, Yamazato Y, Sun C, Diez-Freire C, Raizada MK (2007) Overexpression of angiotensin-converting enzyme 2 in the rostral ventrolateral medulla causes long-term decrease in blood pressure in the spontaneously hypertensive rats. Hypertension 49:926–931PubMedCrossRefGoogle Scholar
  55. 55.
    Feng Y, Xia H, Cai Y, Halabi CM, Becker LK, Santos RA, Speth RC, Sigmund CD, Lazartigues E (2010) Brain-selective overexpression of human Angiotensin-converting enzyme type 2 attenuates neurogenic hypertension. Circ Res 106:373–382PubMedCrossRefGoogle Scholar
  56. 56.
    Thomas MC, Pickering RJ, Tsorotes D, Koitka A, Sheehy K, Bernardi S, Toffoli B, Nguyen-Huu TP, Head GA, Fu Y, Chin-Dusting J, Cooper ME, Tikellis C (2010) Genetic Ace2 deficiency accentuates vascular inflammation and atherosclerosis in the ApoE knockout mouse. Circ Res 107:888–897PubMedCrossRefGoogle Scholar
  57. 57.
    Zhang C, Zhao YX, Zhang YH, Zhu L, Deng BP, Zhou ZL, Li SY, Lu XT, Song LL, Lei XM, Tang WB, Wang N, Pan CM, Song HD, Liu CX, Dong B, Zhang Y, Cao Y (2010) Angiotensin-converting enzyme 2 attenuates atherosclerotic lesions by targeting vascular cells. Proc Natl Acad Sci USA 107:15886–15891PubMedCrossRefGoogle Scholar
  58. 58.
    Zisman LS, Meixell GE, Bristow MR, Canver CC (2003) Angiotensin-(1-7) formation in the intact human heart: in vivo dependence on angiotensin II as substrate. Circulation 108:1679–1681PubMedCrossRefGoogle Scholar
  59. 59.
    Zisman LS, Keller RS, Weaver B, Lin Q, Speth R, Bristow MR, Canver CC (2003) Increased angiotensin-(1-7)-forming activity in failing human heart ventricles: evidence for upregulation of the angiotensin-converting enzyme Homologue ACE2. Circulation 108:1707–1712PubMedCrossRefGoogle Scholar
  60. 60.
    Campbell DJ, Zeitz CJ, Esler MD, Horowitz JD (2004) Evidence against a major role for angiotensin converting enzyme-related carboxypeptidase (ACE2) in angiotensin peptide metabolism in the human coronary circulation. J Hypertens 22:1971–1976PubMedCrossRefGoogle Scholar
  61. 61.
    Brosnihan KB, Li P, Tallant EA, Ferrario CM (1998) Angiotensin-(1-7): a novel vasodilator of the coronary circulation. Biol Res 31:227–234PubMedGoogle Scholar
  62. 62.
    Jackman HL, Massad MG, Sekosan M, Tan F, Brovkovych V, Marcic BM, Erdös EG (2002) Angiotensin 1–9 and 1-7 release in human heart: role of cathepsin A. Hypertension 39:976–981PubMedCrossRefGoogle Scholar
  63. 63.
    Ren Y, Garvin JL, Carretero OA (2002) Vasodilator action of angiotensin-(1-7) on isolated rabbit afferent arterioles. Hypertension 39:799–802PubMedCrossRefGoogle Scholar
  64. 64.
    Grobe JL, Mecca AP, Lingis M, Shenoy V, Bolton TA, Machado JM, Speth RC, Raizada MK, Katovich MJ (2007) Prevention of angiotensin II-induced cardiac remodeling by angiotensin-(1-7). Am J Physiol Heart Circ Physiol 292:H736–H742PubMedCrossRefGoogle Scholar
  65. 65.
    Wang Y, Qian C, Roks AJ, Westermann D, Schumacher SM, Escher F, Schoemaker RG, Reudelhuber TL, van Gilst WH, Schultheiss HP, Tschöpe C, Walther T (2010) Circulating rather than cardiac angiotensin-(1-7) stimulates cardioprotection after myocardial infarction. Circ Heart Fail 3:286–293PubMedCrossRefGoogle Scholar
  66. 66.
    De Mello WC, Ferrario CM, Jessup JA (2007) Beneficial versus harmful effects of Angiotensin (1-7) on impulse propagation and cardiac arrhythmias in the failing heart. J Renin Angiotensin Aldosterone Syst 8:74–80PubMedCrossRefGoogle Scholar
  67. 67.
    Kostenis E, Milligan G, Christopoulos A, Sanchez-Ferrer CF, Heringer-Walther S, Sexton PM, Gembardt F, Kellett E, Martini L, Vanderheyden P, Schultheiss HP, Walther T (2005) G-protein-coupled receptor Mas is a physiological antagonist of the angiotensin II type 1 receptor. Circulation 111:1806–1813PubMedCrossRefGoogle Scholar
  68. 68.
    Urata H, Healy B, Stewart RW, Bumpus FM, Husain A (1990) Angiotensin II-forming pathways in normal and failing human hearts. Circ Res 66:883–890PubMedGoogle Scholar
  69. 69.
    Urata H, Kinoshita A, Misono KS, Bumpus FM, Husain A (1990) Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J Biol Chem 265:22348–22357PubMedGoogle Scholar
  70. 70.
    Jenne DE, Tschopp J (1991) Angiotensin II-forming heart chymase is a mast-cell-specific enzyme. Biochem J 276:567–568PubMedGoogle Scholar
  71. 71.
    Mackins CJ, Kano S, Seyedi N, Schäfer U, Reid AC, Machida T, Silver RB, Levi R (2006) Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion. J Clin Invest 116:1063–1070PubMedCrossRefGoogle Scholar
  72. 72.
    Hara M, Ono K, Hwang MW, Iwasaki A, Okada M, Nakatani K, Sasayama S, Matsumori A (2002) Evidence for a role of mast cells in the evolution to congestive heart failure. J Exp Med 195:375–381PubMedCrossRefGoogle Scholar
  73. 73.
    Juillerat L, Nussberger J, Ménard J, Mooser V, Christen Y, Waeber B, Graf P, Brunner HR (1990) Determinants of angiotensin II generation during converting enzyme inhibition. Hypertension 16:564–572PubMedGoogle Scholar
  74. 74.
    van de Wal RM, Plokker HW, Lok DJ, Boomsma F, van der Horst FA, van Veldhuisen DJ, van Gilst WH, Voors AA (2006) Determinants of increased angiotensin II levels in severe chronic heart failure patients despite ACE inhibition. Int J Cardiol 106:367–372PubMedCrossRefGoogle Scholar
  75. 75.
    Roig E, Perez-Villa F, Morales M, Jiménez W, Orús J, Heras M, Sanz G (2000) Clinical implications of increased plasma angiotensin II despite ACE inhibitor therapy in patients with congestive heart failure. Eur Heart J 21:53–57PubMedCrossRefGoogle Scholar
  76. 76.
    Wiemer G, Dobrucki LW, Louka FR, Malinski T, Heitsch H (2002) AVE 0991, a nonpeptide mimic of the effects of angiotensin-(1-7) on the endothelium. Hypertension 40:847–852PubMedCrossRefGoogle Scholar
  77. 77.
    Hernández Prada JA, Ferreira AJ, Katovich MJ, Shenoy V, Qi Y, Santos RA, Castellano RK, Lampkins AJ, Gubala V, Ostrov DA, Raizada MK (2008) Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents. Hypertension 51:1312–1317PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Wang Wang
    • 1
    • 2
  • Sreedhar Bodiga
    • 2
    • 3
  • Subhash K. Das
    • 2
    • 3
  • Jennifer Lo
    • 2
    • 3
  • Vaibhav Patel
    • 2
    • 3
  • Gavin Y. Oudit
    • 1
    • 2
    • 3
  1. 1.Department of PhysiologyUniversity of AlbertaEdmontonCanada
  2. 2.Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart InstituteUniversity of AlbertaEdmontonCanada
  3. 3.Mazankowski Alberta Heart InstituteUniversity of AlbertaEdmontonCanada

Personalised recommendations