Current Heart Failure Reports

, Volume 8, Issue 3, pp 176–183 | Cite as

Recombinant Human Angiotensin-Converting Enzyme 2 as a New Renin-Angiotensin System Peptidase for Heart Failure Therapy

Article

Abstract

Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that metabolizes several peptides, including the degradation of angiotensin (Ang) II, a peptide with vasoconstrictive/proliferative effects, to generate Ang 1-7, which exerts vasodilatory/antiproliferative actions by acting through its receptor Mas. ACE2 is a multifunctional enzyme, and its actions on other vasoactive peptides, including the apelin-13 and apelin-17 peptides, also can contribute to its cardiovascular effects. The classical pathway of the renin-angiotensin system involving the ACE-Ang II-Ang II type-1 receptor axis is antagonized by the second arm 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. Human recombinant ACE2 also is a negative regulator of Ang II–induced myocardial hypertrophy, fibrosis, and diastolic dysfunction and suppresses pressure overload–induced heart failure. Due to its characteristics, the ACE2/Ang 1-7/Mas axis may represent new possibilities for developing novel therapeutic strategies for the treatment of hypertension and heart failure. This review summarizes the beneficial effects of ACE2 in heart disease and the potential use of human recombinant ACE2 as a novel therapy for heart failure.

Keywords

Angiotensin converting enzyme 2 ACE2 Angiotensin 1-7 Ang 1-7 Angiotensin II Ang II NADPH oxidase Diastolic dysfunction Chymase Signaling Myocardial fibrosis Hypertrophy Heart failure Therapy Recombinant human angiotensin converting enzyme 2 RhACE2 Diastolic dysfunction 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Roger VL, Go AS, Lloyd-Jones DM, et al. Executive Summary: Heart Disease and Stroke Statistics–2011 Update: A Report From the American Heart Association. Circulation. 2011;123:459–63.CrossRefGoogle Scholar
  2. 2.
    Zaman MA, Oparil S, Calhoun DA. Drugs targeting the renin-angiotensin-aldosterone system. Nat Rev Drug Discov. 2002;1:621–36.PubMedCrossRefGoogle Scholar
  3. 3.
    Tipnis SR, Hooper NM, Hyde R, et al. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000;275:33238–43.PubMedCrossRefGoogle Scholar
  4. 4.
    Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res. 2000;87:E1–9.PubMedGoogle Scholar
  5. 5.
    Crackower MA, Sarao R, Oudit GY, et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature. 2002;417:822–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Oudit GY, Kassiri Z, Patel MP, et al. Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice. Cardiovasc Res. 2007;75:29–39.PubMedCrossRefGoogle Scholar
  7. 7.
    •• Zhong JC, Basu R, Guo D, et al. Angiotensin converting enzyme 2 suppresses pathological hypertrophy, myocardial fibrosis and cardiac dysfunction. Circulation. 2010;122:717–28. This study provides definitive evidence for a critical role of ACE2 in metabolizing Ang II into Ang 1-7 in vivo and for the role of ACE2 in controlling Ang II–induced cardiac dysfunction and the potential therapeutic potential of rhACE2 in a pressure-overload model of heart failure.PubMedCrossRefGoogle Scholar
  8. 8.
    • Bodiga S, Zhong JC, Wang W, et al. Enhanced susceptibility to biomechanical stress in ACE2 null mice is prevented by loss of the p47phox NADPH oxidase subunit. Cardiovasc Res 2011; doi:10.1093/cvr/cvr036. A pivotal mechanistic link is provided between ACE2 deficiency and increased activation of the NADPH oxidase system, mediated primarily by the p47phox subunit. Ang 1-7 was capable of suppressing the increased NADPH oxidase activity.
  9. 9.
    Lovren F, Pan Y, Quan A, et al. Angiotensin converting enzyme-2 confers endothelial protection and attenuates atherosclerosis. Am J Physiol Heart Circ Physiol. 2008;295:H1377–84.PubMedCrossRefGoogle Scholar
  10. 10.
    Rentzsch B, Todiras M, Iliescu R, et al. Transgenic angiotensin-converting enzyme 2 overexpression in vessels of SHRSP rats reduces blood pressure and improves endothelial function. Hypertension. 2008;52:967–73.PubMedCrossRefGoogle Scholar
  11. 11.
    Wysocki J, Ye M, Rodriguez E, et al. Targeting the degradation of angiotensin II with recombinant angiotensin-converting enzyme 2: prevention of angiotensin II-dependent hypertension. Hypertension. 2009;55:90–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Oudit GY, Herzenberg AM, Kassiri Z, et al. Loss of angiotensin-converting enzyme-2 leads to the late development of angiotensin II-dependent glomerulosclerosis. Am J Pathol. 2006;168:1808–20.PubMedCrossRefGoogle Scholar
  13. 13.
    Oudit GY, Liu GC, Zhong J, et al. Human recombinant ACE2 reduces the progression of diabetic nephropathy. Diabetes. 2010;59:529–38.PubMedCrossRefGoogle Scholar
  14. 14.
    Zhong J, Guo D, Chen CB, et al. Prevention of angiotensin ii-mediated renal oxidative stress, inflammation, and fibrosis by angiotensin-converting enzyme 2. Hypertension. 2011;57:314–22.PubMedCrossRefGoogle Scholar
  15. 15.
    Vickers C, Hales P, Kaushik V, et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem. 2002;277:14838–43.PubMedCrossRefGoogle Scholar
  16. 16.
    Santos RA, Silva AC Simoes e, Maric C, et al. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA. 2003;100:8258–63.PubMedCrossRefGoogle Scholar
  17. 17.
    • Mercure C, Yogi A, Callera GE, et al. Angiotensin(1-7) blunts hypertensive cardiac remodeling by a direct effect on the heart. Circ Res. 2008;103:1319–26. This study provides definitive proof that Ang 1-7 mediates antiremodeling effects and, therefore, the product of ACE2 action (Ang 1-7) mediates a cardioprotective role in a model of heart failure.PubMedCrossRefGoogle Scholar
  18. 18.
    Garabelli PJ, Modrall JG, Penninger JM, et al. Distinct roles for angiotensin-converting enzyme 2 and carboxypeptidase A in the processing of angiotensins within the murine heart. Exp Physiol. 2008;93:613–21.PubMedCrossRefGoogle Scholar
  19. 19.
    Kassiri Z, Zhong J, Guo D, et al. Loss of angiotensin-converting enzyme 2 accelerates maladaptive left ventricular remodeling in response to myocardial infarction. Circ Heart Fail. 2009;2:446–55.PubMedCrossRefGoogle Scholar
  20. 20.
    Santos RA, Ferreira AJ, Pinheiro SV, et al. Angiotensin-(1-7) and its receptor as a potential targets for new cardiovascular drugs. Expert Opin Investig Drugs. 2005;14:1019–31.PubMedCrossRefGoogle Scholar
  21. 21.
    Lee DK, Cheng R, Nguyen T, et al. Characterization of apelin, the ligand for the APJ receptor. J Neurochem. 2000;74:34–41.PubMedCrossRefGoogle Scholar
  22. 22.
    Pitkin SL, Maguire JJ, Bonner TI, Davenport AP. International union of basic and clinical pharmacology. LXXIV. Apelin receptor nomenclature, distribution, pharmacology, and function. Pharmacol Rev. 2010;62:331–42.PubMedCrossRefGoogle Scholar
  23. 23.
    Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006;355:260–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355:251–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: Part II: causal mechanisms and treatment. Circulation. 2002;105:1503–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Iwata M, Cowling RT, Gurantz D, et al. Angiotensin-(1-7) binds to specific receptors on cardiac fibroblasts to initiate antifibrotic and antitrophic effects. Am J Physiol Heart Circ Physiol. 2005;289:H2356–63.PubMedCrossRefGoogle Scholar
  27. 27.
    Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation. 1991;83:1849–65.PubMedGoogle Scholar
  28. 28.
    Grobe JL, Der Sarkissian S, Stewart JM, et al. ACE2 overexpression inhibits hypoxia-induced collagen production by cardiac fibroblasts. Clin Sci Lond. 2007;113(8):357–64.PubMedCrossRefGoogle Scholar
  29. 29.
    Huentelman MJ, Grobe JL, Vazquez J, et al. Protection from angiotensin II-induced cardiac hypertrophy and fibrosis by systemic lentiviral delivery of ACE2 in rats. Exp Physiol. 2005;90:783–90.PubMedCrossRefGoogle Scholar
  30. 30.
    Gurley SB, Allred A, Le TH, et al. Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice. J Clin Invest. 2006;116(8):2218–25.PubMedCrossRefGoogle Scholar
  31. 31.
    Goulter AB, Goddard MJ, Allen JC, Clark KL. ACE2 gene expression is up-regulated in the human failing heart. BMC Med. 2004;2:19.PubMedCrossRefGoogle Scholar
  32. 32.
    Ishiyama Y, Gallagher PE, Averill DB, et al. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension. 2004;43:970–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Burrell LM, Risvanis J, Kubota E, et al. Myocardial infarction increases ACE2 expression in rat and humans. Eur Heart J. 2005;26:369–75.PubMedCrossRefGoogle Scholar
  34. 34.
    Yamamoto K, Ohishi M, Katsuya T, et al. Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II. Hypertension. 2006;47:718–26.PubMedCrossRefGoogle Scholar
  35. 35.
    Kassiri Z, Khokha R. Myocardial extra-cellular matrix and its regulation by metalloproteinases and their inhibitors. Thromb Haemost. 2005;93:212–9.PubMedGoogle Scholar
  36. 36.
    Zhao YX, Yin HQ, Yu QT, et al. ACE2 overexpression ameliorates left ventricular remodeling and dysfunction in a rat model of myocardial infarction. Hum Gene Ther. 2010;21:1545–54.PubMedCrossRefGoogle Scholar
  37. 37.
    Lieb W, Graf J, Gotz A, et al. 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. 2006;84:88–96.PubMedCrossRefGoogle Scholar
  38. 38.
    Yang W, Huang W, Su S, et al. 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. 2006;111:333–40.PubMedCrossRefGoogle Scholar
  39. 39.
    Keidar S, Strizevsky A, Raz A, Gamliel-Lazarovich A. ACE2 activity is increased in monocyte-derived macrophages from prehypertensive subjects. Nephrol Dial Transplant. 2007;22:597–601.PubMedCrossRefGoogle Scholar
  40. 40.
    Zhong J, Yan Z, Liu D, et al. Association of angiotensin-converting enzyme 2 gene A/G polymorphism and elevated blood pressure in Chinese patients with metabolic syndrome. J Lab Clin Med. 2006;147:91–5.PubMedCrossRefGoogle Scholar
  41. 41.
    • Epelman S, Shrestha K, Troughton RW, et al. Soluble angiotensin-converting enzyme 2 in human heart failure: relation with myocardial function and clinical outcomes. J Card Fail. 2009;15:565–71. This is the first clinical study to show that plasma ACE2 is elevated in patients with heart failure and correlates this with adverse clinical outcomes.PubMedCrossRefGoogle Scholar
  42. 42.
    Wang Y, Moreira Mda C, Heringer-Walther S, et al. Plasma ACE2 activity is an independent prognostic marker in Chagas’ disease and equally potent as BNP. J Card Fail. 2010;16:157–63.PubMedCrossRefGoogle Scholar
  43. 43.
    Carretero OA, Oparil S. Essential hypertension. Part I: definition and etiology. Circulation. 2000;101:329–35.PubMedGoogle Scholar
  44. 44.
    Stoll M, Jacob HJ. Genetic rat models of hypertension: relationship to human hypertension. Curr Hypertens Rep. 2001;3:157–64.PubMedCrossRefGoogle Scholar
  45. 45.
    Oudit GY, Crackower MA, Backx PH, Penninger JM. The role of ACE2 in cardiovascular physiology. Trends Cardiovasc Med. 2003;13:93–101.PubMedCrossRefGoogle Scholar
  46. 46.
    Yamazato M, Yamazato Y, Sun C, et al. Overexpression of angiotensin-converting enzyme 2 in the rostral ventrolateral medulla causes long-term decrease in blood pressure in the spontaneously hypertensive rats. Hypertension. 2007;49:926–31.PubMedCrossRefGoogle Scholar
  47. 47.
    Feng Y, Xia H, Cai Y, et al. Brain-selective overexpression of human Angiotensin-converting enzyme type 2 attenuates neurogenic hypertension. Circ Res. 2010;106:373–82.PubMedCrossRefGoogle Scholar
  48. 48.
    Thomas MC, Pickering RJ, Tsorotes D, et al. Genetic Ace2 deficiency accentuates vascular inflammation and atherosclerosis in the ApoE knockout mouse. Circ Res. 2010;107:888–97.PubMedCrossRefGoogle Scholar
  49. 49.
    Zhang C, Zhao YX, Zhang YH, et al. Angiotensin-converting enzyme 2 attenuates atherosclerotic lesions by targeting vascular cells. Proc Natl Acad Sci USA. 2010;107:15886–91.PubMedCrossRefGoogle Scholar
  50. 50.
    Sampaio WO, Henrique Dde Castro C, Santos RA, et al. Angiotensin-(1-7) counterregulates angiotensin II signaling in human endothelial cells. Hypertension. 2007;50:1093–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Sampaio WO, Souza dos Santos RA, Faria-Silva R, et al. Angiotensin-(1-7) through receptor Mas mediates endothelial nitric oxide synthase activation via Akt-dependent pathways. Hypertension. 2007;49:185–92.PubMedCrossRefGoogle Scholar
  52. 52.
    Rabelo LA, Xu P, Todiras M, et al. Ablation of angiotensin (1-7) receptor Mas in C57Bl/6 mice causes endothelial dysfunction. J Am Soc Hypertens. 2008;2:418–24.PubMedCrossRefGoogle Scholar
  53. 53.
    Xu P, Costa-Goncalves AC, Todiras M, et al. Endothelial dysfunction and elevated blood pressure in MAS gene-deleted mice. Hypertension. 2008;51:574–80.PubMedCrossRefGoogle Scholar
  54. 54.
    Loot AE, Roks AJ, Henning RH, et al. Angiotensin-(1-7) attenuates the development of heart failure after myocardial infarction in rats. Circulation. 2002;105:1548–50.PubMedCrossRefGoogle Scholar
  55. 55.
    Benter IF, Yousif MH, Dhaunsi GS, et al. Angiotensin-(1-7) prevents activation of NADPH oxidase and renal vascular dysfunction in diabetic hypertensive rats. Am J Nephrol. 2008;28:25–33.PubMedCrossRefGoogle Scholar
  56. 56.
    Benter IF, Yousif MH, Anim JT, et al. Angiotensin-(1-7) prevents development of severe hypertension and end-organ damage in spontaneously hypertensive rats treated with L-NAME. Am J Physiol Heart Circ Physiol. 2006;290:H684–91.PubMedCrossRefGoogle Scholar
  57. 57.
    Grobe JL, Mecca AP, Lingis M, et al. Prevention of angiotensin II-induced cardiac remodeling by angiotensin-(1-7). Am J Physiol Heart Circ Physiol. 2007;292:H736–42.PubMedCrossRefGoogle Scholar
  58. 58.
    Benter IF, Yousif MH, Cojocel C, et al. Angiotensin-(1-7) prevents diabetes-induced cardiovascular dysfunction. Am J Physiol Heart Circ Physiol. 2007;292:H666–72.PubMedCrossRefGoogle Scholar
  59. 59.
    Ebermann L, Spillmann F, Sidiropoulos M, et al. The angiotensin-(1-7) receptor agonist AVE0991 is cardioprotective in diabetic rats. Eur J Pharmacol. 2008;590:276–80.PubMedCrossRefGoogle Scholar
  60. 60.
    Ferreira AJ, Oliveira TL, Castro MC, et al. Isoproterenol-induced impairment of heart function and remodeling are attenuated by the nonpeptide angiotensin-(1-7) analogue AVE 0991. Life Sci. 2007;81:916–23.PubMedCrossRefGoogle Scholar
  61. 61.
    Ferreira AJ, Jacoby BA, Araujo CA, et al. The nonpeptide angiotensin-(1-7) receptor Mas agonist AVE-0991 attenuates heart failure induced by myocardial infarction. Am J Physiol Heart Circ Physiol. 2007;292:H1113–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Santos SH, Braga JF, Mario EG, et al. Improved lipid and glucose metabolism in transgenic rats with increased circulating angiotensin-(1-7). Arterioscler Thromb Vasc Biol. 2010;30:953–61.PubMedCrossRefGoogle Scholar
  63. 63.
    Santos RA, Castro CH, Gava E, et al. Impairment of in vitro and in vivo heart function in angiotensin-(1-7) receptor MAS knockout mice. Hypertension. 2006;47:996–1002.PubMedCrossRefGoogle Scholar
  64. 64.
    Dias-Peixoto MF, Santos RA, Gomes ER, et al. Molecular mechanisms involved in the angiotensin-(1-7)/Mas signaling pathway in cardiomyocytes. Hypertension. 2008;52:542–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Gomes ER, Lara AA, Almeida PW, et al. Angiotensin-(1-7) prevents cardiomyocyte pathological remodeling through a nitric oxide/guanosine 3',5'-cyclic monophosphate-dependent pathway. Hypertension. 2010;55:153–60.PubMedCrossRefGoogle Scholar
  66. 66.
    Tallant EA, Ferrario CM, Gallagher PE. Angiotensin-(1-7) inhibits growth of cardiac myocytes through activation of the mas receptor. Am J Physiol Heart Circ Physiol. 2005;289:H1560–6.PubMedCrossRefGoogle Scholar
  67. 67.
    Urata H, Healy B, Stewart RW, et al. Angiotensin II-forming pathways in normal and failing human hearts. Circ Res. 1990;66:883–90.PubMedGoogle Scholar
  68. 68.
    Urata H, Kinoshita A, Misono KS, et al. Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J Biol Chem. 1990;265:22348–57.PubMedGoogle Scholar
  69. 69.
    Jenne DE, Tschopp J. Angiotensin II-forming heart chymase is a mast-cell-specific enzyme. Biochem J. 1991;276:567–8.PubMedGoogle Scholar
  70. 70.
    •• Wei CC, Hase N, Inoue Y, et al. Mast cell chymase limits the cardiac efficacy of Ang I-converting enzyme inhibitor therapy in rodents. J Clin Invest. 2010;120:1229–39. Although biochemical evidence existed for chymase-mediated Ang II formation, this study provides definitive in vivo proof that chymase provides an ACE-independent pathway for the formation of Ang II in the heart.PubMedCrossRefGoogle Scholar
  71. 71.
    Mackins CJ, Kano S, Seyedi N, et al. Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion. J Clin Invest. 2006;116:1063–70.PubMedCrossRefGoogle Scholar
  72. 72.
    Hara M, Ono K, Hwang MW, et al. Evidence for a role of mast cells in the evolution to congestive heart failure. J Exp Med. 2002;195:375–81.PubMedCrossRefGoogle Scholar
  73. 73.
    Juillerat L, Nussberger J, Menard J, et al. Determinants of angiotensin II generation during converting enzyme inhibition. Hypertension. 1990;16:564–72.PubMedGoogle Scholar
  74. 74.
    van de Wal RM, Plokker HW, Lok DJ, et al. Determinants of increased angiotensin II levels in severe chronic heart failure patients despite ACE inhibition. Int J Cardiol. 2006;106:367–72.PubMedCrossRefGoogle Scholar
  75. 75.
    Roig E, Perez-Villa F, Morales M, et al. Clinical implications of increased plasma angiotensin II despite ACE inhibitor therapy in patients with congestive heart failure. Eur Heart J. 2000;21:53–7.PubMedCrossRefGoogle Scholar
  76. 76.
    Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005;111:2605–10.PubMedCrossRefGoogle Scholar
  77. 77.
    Ocaranza MP, Godoy I, Jalil JE, et al. Enalapril attenuates downregulation of Angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat. Hypertension. 2006;48:572–8.PubMedCrossRefGoogle Scholar
  78. 78.
    Zhong JC, Ye JY, Jin HY, et al. Telmisartan attenuates aortic hypertrophy in hypertensive rats by the modulation of ACE2 and profilin-1 expression. Regul Pept. 2011;166:90–7.PubMedCrossRefGoogle Scholar
  79. 79.
    Keidar S, Gamliel-Lazarovich A, Kaplan M, et al. Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients. Circ Res. 2005;97:946–53.PubMedCrossRefGoogle Scholar
  80. 80.
    Lambert DW, Yarski M, Warner FJ, et al. 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. 2005;280:30113–9.PubMedCrossRefGoogle Scholar
  81. 81.
    Iwata M, Silva Enciso JE, Greenberg BH. elective and specific regulation of ectodomain shedding of angiotensin-converting enzyme 2 by tumor necrosis factor alpha-converting enzyme. Am J Physiol Cell Physiol. 2009;297:C1318–29.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Physiology, Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart InstituteUniversity of AlbertaEdmontonCanada
  2. 2.Institute of Molecular BiotechnologyViennaAustria

Personalised recommendations