Current Hypertension Reports

, Volume 15, Issue 1, pp 31–38 | Cite as

Opportunities for Targeting the Angiotensin-Converting Enzyme 2/Angiotensin-(1-7)/Mas Receptor Pathway in Hypertension

  • Rodrigo Araujo Fraga-Silva
  • Anderson Jose Ferreira
  • Robson Augusto Souza dos SantosEmail author
Hypertension and the Kidney (RM Carey and A Mimran, Section Editors)


It is well known that the renin-angiotensin system (RAS) plays a pivotal role in the pathophysiology of cardiovascular diseases. This is well illustrated by the great success of ACE inhibitors and angiotensin (Ang) II AT1 blockers in the treatment of hypertension and its complications. In the past decade, the classical concept of RAS orchestrated by a series of enzymatic reactions culminating in the linear generation and action of Ang II has expanded and become more complex. From the discoveries of new components such as the angiotensin converting enzyme 2 and the receptor Mas emerged a novel concept of dual opposite branches of the RAS: one vasoconstrictor and pro-hypertensive composed of ACE/Ang II/AT1; and other vasodilator and anti-hypertensive composed of ACE2/Ang-(1-7)/Mas. In this review we will discuss recent findings concerning the biological role of the ACE2/Ang-(1-7)/Mas arm in the cardiovascular system and highlight the initiatives to develop potential therapeutic strategies based on this axis for treating hypertension.


Renin-angiotensin system RAS Angiotensin-(1-7) Angiotensin converting enzyme 2 Mas receptor Hypertension 



Dr. R.A. Fraga-Silva: grant from the Brazilian Swiss Joint Research Program. Dr. A.J. Ferreira: none. Dr. R.A.S. Santos: one of the authors of the patent “Process of Preparation of Formulations of the Peptide Angiotensin-(1-7) and its Analogues, Agonistic and Antagonists Using Cyclodextrins, Lipossomes and Biodegradable Polymers and/or Mixtures and Products Thereof” - WO/2003/039434.


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

  1. 1.
    Unger T. The role of the renin-angiotensin system in the development of cardiovascular disease. Am J Cardiol. 2002;89(2A):3A–9. discussion 10A.PubMedCrossRefGoogle Scholar
  2. 2.
    Bader M. Tissue renin-angiotensin-aldosterone systems: targets for pharmacological therapy. Annu Rev Pharmacol Toxicol. 2010;50:439–65.PubMedCrossRefGoogle Scholar
  3. 3.
    Nicholls MG, Richards AM, Agarwal M. The importance of the renin-angiotensin system in cardiovascular disease. J Hum Hypertens. 1998;12(5):295–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Schiffrin EL. Vascular and cardiac benefits of angiotensin receptor blockers. Am J Med. 2002;113(5):409–18.PubMedCrossRefGoogle Scholar
  5. 5.
    Ma TK, et al. Renin-angiotensin-aldosterone system blockade for cardiovascular diseases: current status. Br J Pharmacol. 2010;160(6):1273–92.PubMedCrossRefGoogle Scholar
  6. 6.
    Matsusaka T, Ichikawa I. Biological functions of angiotensin and its receptors. Annu Rev Physiol. 1997;59:395–412.PubMedCrossRefGoogle Scholar
  7. 7.
    Allen AM, Zhuo J, Mendelsohn FA. Localization and function of angiotensin AT1 receptors. Am J Hypertens. 2000;13(1 Pt 2):31S–8.PubMedCrossRefGoogle Scholar
  8. 8.
    de Gasparo M, et al. International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev. 2000;52(3):415–72.PubMedGoogle Scholar
  9. 9.
    Vickers C, et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem. 2002;277(17):14838–43.PubMedCrossRefGoogle Scholar
  10. 10.
    Tipnis SR, et al. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000;275(43):33238–43.PubMedCrossRefGoogle Scholar
  11. 11.
    Donoghue M, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000;87(5):E1–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Santos RA, et al. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci U S A. 2003;100(14):8258–63.PubMedCrossRefGoogle Scholar
  13. 13.
    Zisman LS, et al. Angiotensin-(1-7) formation in the intact human heart: in vivo dependence on angiotensin II as substrate. Circulation. 2003;108(14):1679–81.PubMedCrossRefGoogle Scholar
  14. 14.
    Ferrario CM, et al. Counterregulatory actions of angiotensin-(1-7). Hypertension. 1997;30(3 Pt 2):535–41.PubMedCrossRefGoogle Scholar
  15. 15.
    Ferreira AJ, et al. Therapeutic implications of the vasoprotective axis of the renin-angiotensin system in cardiovascular diseases. Hypertension. 2010;55(2):207–13.PubMedCrossRefGoogle Scholar
  16. 16.
    Ferreira AJ, et al. New cardiovascular and pulmonary therapeutic strategies based on the angiotensin-converting enzyme 2/angiotensin-(1-7)/mas receptor axis. Int J Hypertens. 2012;2012:147825.PubMedGoogle Scholar
  17. 17.
    Bindom SM, Lazartigues E. The sweeter side of ACE2: physiological evidence for a role in diabetes. Mol Cell Endocrinol. 2009;302(2):193–202.PubMedCrossRefGoogle Scholar
  18. 18.
    Ferreira AJ, Santos RA. Cardiovascular actions of angiotensin-(1-7). Braz J Med Biol Res. 2005;38(4):499–507.PubMedCrossRefGoogle Scholar
  19. 19.
    Santos RA, Ferreira AJ, Simoes ESAC. Recent advances in the angiotensin-converting enzyme 2-angiotensin(1-7)-Mas axis. Exp Physiol. 2008;93(5):519–27.PubMedCrossRefGoogle Scholar
  20. 20.
    Kokubu T, et al. Purification and properties of angiotensin I-converting enzyme in human lung and its role on the metabolism of vasoactive peptides in pulmonary circulation. Adv Exp Med Biol. 1979;120B:467–75.PubMedGoogle Scholar
  21. 21.
    Touyz RM, Berry C. Recent advances in angiotensin II signaling. Braz J Med Biol Res. 2002;35(9):1001–15.PubMedCrossRefGoogle Scholar
  22. 22.
    Steckelings UM, Unger T. Angiotensin II type 2 receptor agonists–where should they be applied? Expert Opin Investig Drugs. 2012;21(6):763–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Widdop RE, et al. AT2 receptor-mediated relaxation is preserved after long-term AT1 receptor blockade. Hypertension. 2002;40(4):516–20.PubMedCrossRefGoogle Scholar
  24. 24.
    Savoia C, et al. Angiotensin type 2 receptor in hypertensive cardiovascular disease. Curr Opin Nephrol Hypertens. 2011;20(2):125–32.PubMedCrossRefGoogle Scholar
  25. 25.
    Fyhrquist F, Saijonmaa O. Renin-angiotensin system revisited. J Intern Med. 2008;264(3):224–36.PubMedCrossRefGoogle Scholar
  26. 26.
    Bosnyak S, et al. Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors. Clin Sci (Lond). 2011;121(7):297–303.Google Scholar
  27. 27.
    Albiston AL, et al. Evidence that the angiotensin IV (AT(4)) receptor is the enzyme insulin-regulated aminopeptidase. J Biol Chem. 2001;276(52):48623–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Chai SY, et al. The angiotensin IV/AT4 receptor. Cell Mol Life Sci. 2004;61(21):2728–37.PubMedCrossRefGoogle Scholar
  29. 29.
    Schiavone MT, et al. Release of vasopressin from the rat hypothalamo-neurohypophysial system by angiotensin-(1-7) heptapeptide. Proc Natl Acad Sci U S A. 1988;85(11):4095–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Rice GI, et al. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. 2004;383(Pt 1):45–51.PubMedGoogle Scholar
  31. 31.
    Brosnihan KB, Li P, Ferrario CM. Angiotensin-(1-7) dilates canine coronary arteries through kinins and nitric oxide. Hypertension. 1996;27(3 Pt 2):523–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Sampaio WO, Nascimento AA, Santos RA. Systemic and regional hemodynamic effects of angiotensin-(1-7) in rats. Am J Physiol Heart Circ Physiol. 2003;284(6):H1985–94.PubMedGoogle Scholar
  33. 33.
    Freeman EJ, et al. Angiotensin-(1-7) inhibits vascular smooth muscle cell growth. Hypertension. 1996;28(1):104–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Gava E, et al. Angiotensin-(1-7) receptor Mas is an essential modulator of extracellular matrix protein expression in the heart. Regul Pept. 2012;175(1–3):30–42.PubMedCrossRefGoogle Scholar
  35. 35.
    Xu P, et al. Endothelial dysfunction and elevated blood pressure in MAS gene-deleted mice. Hypertension. 2008;51(2):574–80.PubMedCrossRefGoogle Scholar
  36. 36.
    Rabelo LA, Alenina N, Bader M. ACE2-angiotensin-(1-7)-Mas axis and oxidative stress in cardiovascular disease. Hypertens Res. 2011;34(2):154–60.PubMedCrossRefGoogle Scholar
  37. 37.
    Fraga-Silva RA, et al. The antithrombotic effect of angiotensin-(1-7) involves mas-mediated NO release from platelets. Mol Med. 2008;14(1–2):28–35.PubMedGoogle Scholar
  38. 38.
    •• Fraga-Silva RA, et al. An orally active formulation of angiotensin-(1-7) produces an antithrombotic effect. Clinics (Sao Paulo). 2011;66(5):837–41. This work shows that the oral formulations Ang-(1-7)-CyD produces biological activity through increasing Ang-(1-7) plasma level and in a Mas-dependent manner.CrossRefGoogle Scholar
  39. 39.
    Fraga-Silva RA, et al. The angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptor axis: a potential target for treating thrombotic diseases. Thromb Haemost. 2012;108(6). doi: 10.1160/TH12-06-0396.
  40. 40.
    Santos RA, Campagnole-Santos MJ, Andrade SP. Angiotensin-(1-7): an update. Regul Pept. 2000;91(1–3):45–62.PubMedCrossRefGoogle Scholar
  41. 41.
    Silva DM, et al. Evidence for a new angiotensin-(1-7) receptor subtype in the aorta of Sprague-Dawley rats. Peptides. 2007;28(3):702–7.PubMedCrossRefGoogle Scholar
  42. 42.
    •• Verano-Braga T, et al. Time-resolved quantitative phosphoproteomics: new insights into angiotensin-(1-7) signaling networks in human endothelial cells. J Proteome Res. 2012;11(6):3370–81. This study provides new concepts and new understanding of the Ang-(17) signal transduction, shedding light on the mechanisms underlying Mas activation. Google Scholar
  43. 43.
    Heitsch H, et al. Angiotensin-(1-7)-stimulated nitric oxide and superoxide release from endothelial cells. Hypertension. 2001;37(1):72–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Sampaio WO, et al. Angiotensin-(1-7) through receptor Mas mediates endothelial nitric oxide synthase activation via Akt-dependent pathways. Hypertension. 2007;49(1):185–92.PubMedCrossRefGoogle Scholar
  45. 45.
    Sampaio WO, et al. Angiotensin-(1-7) counterregulates angiotensin II signaling in human endothelial cells. Hypertension. 2007;50(6):1093–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Greer EL, Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 2005;24(50):7410–25.PubMedCrossRefGoogle Scholar
  47. 47.
    Zhao Y, Wang Y, Zhu WG. Applications of post-translational modifications of FoxO family proteins in biological functions. J Mol Cell Biol. 2011;3(5):276–82.PubMedCrossRefGoogle Scholar
  48. 48.
    Brunet A, et al. Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell. 1999;96(6):857–68.PubMedCrossRefGoogle Scholar
  49. 49.
    Zhu Z, et al. Angiotensin-(1-7) inhibits angiotensin II-induced signal transduction. J Cardiovasc Pharmacol. 2002;40(5):693–700.PubMedCrossRefGoogle Scholar
  50. 50.
    Giani JF, et al. Angiotensin-(1-7) has a dual role on growth-promoting signalling pathways in rat heart in vivo by stimulating STAT3 and STAT5a/b phosphorylation and inhibiting angiotensin II-stimulated ERK1/2 and Rho kinase activity. Exp Physiol. 2008;93(5):570–8.PubMedGoogle Scholar
  51. 51.
    Mercure C, et al. Angiotensin(1-7) blunts hypertensive cardiac remodeling by a direct effect on the heart. Circ Res. 2008;103(11):1319–26.PubMedCrossRefGoogle Scholar
  52. 52.
    Gomes ER, et al. Angiotensin-(1-7) prevents cardiomyocyte pathological remodeling through a nitric oxide/guanosine 3',5'-cyclic monophosphate-dependent pathway. Hypertension. 2010;55(1):153–60.PubMedCrossRefGoogle Scholar
  53. 53.
    Iyer SN, Ferrario CM, Chappell MC. Angiotensin-(1-7) contributes to the antihypertensive effects of blockade of the renin-angiotensin system. Hypertension. 1998;31(1 Pt 2):356–61.PubMedCrossRefGoogle Scholar
  54. 54.
    Iyer SN, et al. Vasodepressor actions of angiotensin-(1-7) unmasked during combined treatment with lisinopril and losartan. Hypertension. 1998;31(2):699–705.PubMedCrossRefGoogle Scholar
  55. 55.
    Collister JP, Hendel MD. The role of Ang (1-7) in mediating the chronic hypotensive effects of losartan in normal rats. J Renin Angiotensin Aldosterone Syst. 2003;4(3):176–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Kucharewicz I, et al. Antithrombotic effect of captopril and losartan is mediated by angiotensin-(1-7). Hypertension. 2002;40(5):774–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Yamada K, et al. Converting enzyme determines plasma clearance of angiotensin-(1-7). Hypertension. 1998;32(3):496–502.PubMedCrossRefGoogle Scholar
  58. 58.
    Wiemer G, et al. AVE 0991, a nonpeptide mimic of the effects of angiotensin-(1-7) on the endothelium. Hypertension. 2002;40(6):847–52.PubMedCrossRefGoogle Scholar
  59. 59.
    Santos RA, Ferreira AJ. Pharmacological effects of AVE 0991, a nonpeptide angiotensin-(1-7) receptor agonist. Cardiovasc Drug Rev. 2006;24(3–4):239–46.PubMedCrossRefGoogle Scholar
  60. 60.
    da Costa-Goncalves AC, et al. AVE 0991, a non-peptide Mas-receptor agonist, facilitates penile erection. Exp Physiol. 2012. doi: 10.1113/expphysiol.2012.068551.
  61. 61.
    Pinheiro SV, et al. Nonpeptide AVE 0991 is an angiotensin-(1-7) receptor Mas agonist in the mouse kidney. Hypertension. 2004;44(4):490–6.PubMedCrossRefGoogle Scholar
  62. 62.
    Lemos VS, et al. The endothelium-dependent vasodilator effect of the nonpeptide Ang(1-7) mimic AVE 0991 is abolished in the aorta of mas-knockout mice. J Cardiovasc Pharmacol. 2005;46(3):274–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Ferreira AJ, 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(2):H1113–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Ferreira AJ, 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(11):916–23.PubMedCrossRefGoogle Scholar
  65. 65.
    Benter IF, 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(2):H684–91.PubMedCrossRefGoogle Scholar
  66. 66.
    Faria-Silva R, Duarte FV, Santos RA. Short-term angiotensin(1-7) receptor MAS stimulation improves endothelial function in normotensive rats. Hypertension. 2005;46(4):948–52.PubMedCrossRefGoogle Scholar
  67. 67.
    Carvalho MB, et al. Evidence for Mas-mediated bradykinin potentiation by the angiotensin-(1-7) nonpeptide mimic AVE 0991 in normotensive rats. Hypertension. 2007;50(4):762–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Singh Y, Singh K, Sharma PL. Effect of combination of renin inhibitor and Mas-receptor agonist in DOCA-salt-induced hypertension in rats. Mol Cell Biochem. 2012. doi: 10.1007/s11010-012-1489-2.
  69. 69.
    Shemesh R, et al. Discovery and validation of novel peptide agonists for G-protein-coupled receptors. J Biol Chem. 2008;283(50):34643–9.PubMedCrossRefGoogle Scholar
  70. 70.
    • Savergnini SQ, et al. Vascular relaxation, antihypertensive effect, and cardioprotection of a novel peptide agonist of the MAS receptor. Hypertension. 2010;56(1):112–20. This recent study was the first indicating that the novel Mas agonist, CGEN-856S, might have a therapeutic value, since it induces vasorelaxation, antihypertensive, and cardioprotective effects.PubMedCrossRefGoogle Scholar
  71. 71.
    Lula I, et al. Study of angiotensin-(1-7) vasoactive peptide and its beta-cyclodextrin inclusion complexes: complete sequence-specific NMR assignments and structural studies. Peptides. 2007;28(11):2199–210.PubMedCrossRefGoogle Scholar
  72. 72.
    Uekama K. Design and evaluation of cyclodextrin-based drug formulation. Chem Pharm Bull (Tokyo). 2004;52(8):900–15.CrossRefGoogle Scholar
  73. 73.
    •• Marques FD, et al. An oral formulation of angiotensin-(1-7) produces cardioprotective effects in infarcted and isoproterenol-treated rats. Hypertension. 2011;57(3):477–83. This work is the first showing the cardioprotective effects of Ang-(1-7) formulation, Ang-(1-7)-CyD.PubMedCrossRefGoogle Scholar
  74. 74.
    • Kluskens LD, et al. Angiotensin-(1-7) with thioether bridge: an angiotensin-converting enzyme-resistant, potent angiotensin-(1-7) analog. J Pharmacol Exp Ther. 2009;328(3):849–54. In this work it was developed the cyclized Ang-(1-7) compound which was proposed as an excellent method to render more resistance against proteolytic breakdown but preserving its activity.PubMedCrossRefGoogle Scholar
  75. 75.
    Durik M, et al. The effect of the thioether-bridged, stabilized Angiotensin-(1-7) analogue cyclic ang-(1-7) on cardiac remodeling and endothelial function in rats with myocardial infarction. Int J Hypertens. 2012;2012:536426.PubMedGoogle Scholar
  76. 76.
    Hernandez Prada JA, et al. Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents. Hypertension. 2008;51(5):1312–7.PubMedCrossRefGoogle Scholar
  77. 77.
    Ferreira AJ, et al. Angiotensin-converting enzyme 2 activation protects against hypertension-induced cardiac fibrosis involving extracellular signal-regulated kinases. Exp Physiol. 2011;96(3):287–94.PubMedCrossRefGoogle Scholar
  78. 78.
    Ferreira AJ, et al. Evidence for angiotensin-converting enzyme 2 as a therapeutic target for the prevention of pulmonary hypertension. Am J Respir Crit Care Med. 2009;179(11):1048–54.PubMedCrossRefGoogle Scholar
  79. 79.
    Fraga-Silva RA, et al. ACE2 activation promotes antithrombotic activity. Mol Med. 2010;16(5–6):210–5.PubMedGoogle Scholar
  80. 80.
    Murca TM, et al. Oral administration of an angiotensin-converting enzyme 2 activator ameliorates diabetes-induced cardiac dysfunction. Regul Pept. 2012;177(1–3):107–15.PubMedCrossRefGoogle Scholar
  81. 81.
    Murca TM, et al. Chronic activation of endogenous angiotensin-converting enzyme 2 protects diabetic rats from cardiovascular autonomic dysfunction. Exp Physiol. 2012;97(6):699–709.PubMedGoogle Scholar
  82. 82.
    Sasaki S, et al. Effects of angiotensin-(1-7) on forearm circulation in normotensive subjects and patients with essential hypertension. Hypertension. 2001;38(1):90–4.PubMedCrossRefGoogle Scholar
  83. 83.
    Davie AP, McMurray JJ. Effect of angiotensin-(1-7) and bradykinin in patients with heart failure treated with an ACE inhibitor. Hypertension. 1999;34(3):457–60.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Rodrigo Araujo Fraga-Silva
    • 1
    • 4
  • Anderson Jose Ferreira
    • 1
    • 3
  • Robson Augusto Souza dos Santos
    • 1
    • 2
    • 5
    Email author
  1. 1.National Institute of Science and Technology in NanobiopharmaceuticsBelo HorizonteBrazil
  2. 2.Department of Physiology and BiophysicsBiological Science Institute, Federal University of Minas GeraisBelo HorizonteBrazil
  3. 3.Department of MorphologyBiological Science Institute, Federal University of Minas GeraisBelo HorizonteBrazil
  4. 4.Institute of Bioengineering, Ecole Polytechnique Fédérale de LausanneLausanneSwitzerland
  5. 5.Departamento de Fisiologia e BiofísicaFederal University of Minas GeraisBelo HorizonteBrazil

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