Devil and angel in the renin-angiotensin system: ACE-angiotensin II-AT1 receptor axis vs. ACE2-angiotensin-(1-7)-Mas receptor axis

Masaru Iwai, Masatsugu Horiuchi, Masaru Iwai, Masatsugu Horiuchi

Abstract

Recent studies have established a new regulatory axis in the renin-angiotensin system (RAS). In this axis, angiotensin (Ang)-(1-7) is finally produced from Ang I or Ang II by the catalytic activity of angiotensin-converting enzyme 2 (ACE2). Ang-(1-7) shows actions different from those of AT(1) receptor stimulation, such as vasodilatation, natriuresis, anti-proliferation and an increase in the bradykinin-NO (nitric oxide) system. As the catalytic efficiency of ACE2 is approximately 400-fold higher with Ang II as a substrate than with Ang I, this axis is possibly acting as a counter-regulatory system against the ACE/Ang II/AT(1) receptor axis. The signaling pathway of the ACE2-Ang-(1-7) axis has not yet been totally and clearly understood. However, a recent report suggests that the Mas oncogene acts as a receptor for Ang-(1-7). Intracellular signaling through Mas is not clear yet. Several factors such as Akt phosphorylation, protein kinase C activation and mitogen-activated protein (MAP) kinase inhibition seem to be involved in this signaling pathway. Further investigations are needed to clarify the regulation and mechanism of action of ACE2 and Ang-(1-7). However, this second axis through ACE2 and Ang-(1-7) in RAS can be an important target for the therapy of cardiovascular and metabolic disorders.

Figures

Figure 1
Figure 1
The role of AT1 receptor stimulation in hypertension and organ damage. NO, nitric oxide; CKD, chronic kidney disease.
Figure 2
Figure 2
The production of angiotensin-(1–7) by the angiotensin-converting enzyme 2 (ACE2).
Figure 3
Figure 3
Action of AT1 and AT2 receptors and Mas-mediated signaling. AT1, angiotensin-II type-1 receptor; AT2, angiotensin-II type-2 receptor; NO, nitric oxide.
Figure 4
Figure 4
The balance between ACE and ACE2 activities affects cardiovascular disorders. ACE, angiotensin-converting enzyme; Ang, angiotensin; AT1, angiotensin-II type-1 receptor; AT2, angiotensin-II type-2 receptor.

References

    1. de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T. International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev. 2000;52:415–472.
    1. Daviet L, Lehtonen JY, Tamura K, Griese DP, Horiuchi M, Dzau VJ. Cloning and characterization of ATRAP, a novel protein that interacts with the angiotensin II type 1 receptor. J Biol Chem. 1999;274:17058–17062. doi: 10.1074/jbc.274.24.17058.
    1. Nouet S, Amzallag N, Li JM, Louis S, Seitz I, Cui TX, Alleaume AM, Di Benedetto M, Boden C, Masson M, Strosberg AD, Horiuchi M, Couraud PO, Nahmias C. Trans-inactivation of receptor tyrosine kinases by novel angiotensin II AT2 receptor-interacting protein, ATIP. J Biol Chem. 2004;279:28989–28997. doi: 10.1074/jbc.M403880200.
    1. Dzau V. The cardiovascular continuum and renin-angiotensin-aldosterone system blockade. J Hypertens Suppl. 2005;23:S9–S17. doi: 10.1097/01.hjh.0000165623.72310.dd.
    1. Kaschina E, Grzesiak A, Li J, Foryst-Ludwig A, Timm M, Rompe F, Sommerfeld M, Kemnitz UR, Curato C, Namsolleck P, Tschöpe C, Hallberg A, Alterman M, Hucko T, Paetsch I, Dietrich T, Schnackenburg B, Graf K, Dahlöf B, Kintscher U, Unger T, Steckelings UM. Angiotensin II type 2 receptor stimulation: a novel option of therapeutic interference with the renin-angiotensin system in myocardial infarction? Circulation. 2008;118:2523–2532. doi: 10.1161/CIRCULATIONAHA.108.784868.
    1. Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000;275:33238–33243. doi: 10.1074/jbc.M002615200.
    1. Santos RA, Ferreira AJ, E Silva AC. Recent advances in the angiotensin-converting enzyme 2-angiotensin(1-7)-Mas axis. Exp Physiol. 2008;93:519–527. doi: 10.1113/expphysiol.2008.042002.
    1. Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007;369:201–207. doi: 10.1016/S0140-6736(07)60108-1.
    1. Murphy TJ, Alexander RW, Griendling KK, Runge MS, Bernstein KE. Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. Nature. 1991;351:233–236. doi: 10.1038/351233a0.
    1. Dzau VJ, Antman EM, Black HR, Hayes DL, Manson JE, Plutzky J, Popma JJ, Stevenson W. The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes: part I: pathophysiology and clinical trial evidence (risk factors through stable coronary artery disease) Circulation. 2006;114:2850–2870. doi: 10.1161/CIRCULATIONAHA.106.655688.
    1. Dzau VJ, Antman EM, Black HR, Hayes DL, Manson JE, Plutzky J, Popma JJ, Stevenson W. The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes: part II: Clinical trial evidence (acute coronary syndromes through renal disease) and future directions. Circulation. 2006;114:2871–2891. doi: 10.1161/CIRCULATIONAHA.106.655761.
    1. Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M, Conti S, Rottoli D, Longaretti L, Cassis P, Morigi M, Coffman TM, Remuzzi G. Disruption of the Ang II type 1 receptor promotes longevity in mice. J Clin Invest. 2009;119:524–530. doi: 10.1172/JCI36703.
    1. Horiuchi M, Hayashida W, Akishita M, Tamura K, Daviet L, Lehtonen JY, Dzau VJ. Stimulation of different subtypes of angiotensin II receptors, AT1 and AT2 receptors, regulates STAT activation by negative crosstalk. Circ Res. 1999;84:876–882. doi: 10.1161/01.RES.84.8.876.
    1. Jones ES, Vinh A, McCarthy CA, Gaspari TA, Widdop RE. AT2 receptors: functional relevance in cardiovascular disease. Pharmacol Ther. 2008;120:292–316. doi: 10.1016/j.pharmthera.2008.08.009.
    1. Carey RM, Padia SH. Angiotensin AT2 receptors: control of renal sodium excretion and blood pressure. Trends Endocrinol Metab. 2008;19:84–87. doi: 10.1016/j.tem.2008.01.003.
    1. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000;87:E1–E9. doi: 10.1161/01.RES.87.5.e1.
    1. 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. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem. 2002;277:14838–14843. doi: 10.1074/jbc.M200581200.
    1. Ferrario CM, Chappell MC, Tallant EA, Brosnihan KB, Diz DI. Counterregulatory actions of angiotensin-(1-7) Hypertension. 1997;30:535–541. doi: 10.1161/01.HYP.30.3.535.
    1. Roks AJ, van Geel PP, Pinto YM, Buikema H, Henning RH, de Zeeuw D, van Gilst WH. Angiotensin-(1-7) is a modulator of the human renin-angiotensin system. Hypertension. 1999;34:296–301. doi: 10.1161/01.HYP.34.2.296.
    1. Brosnihihan KB, Li P, Ferrario CM. Angiotensin-(1-7) dilates canine coronary arteries through kinins and nitric oxide. Hypertension. 1996;27:523–528. doi: 10.1161/01.HYP.27.3.523.
    1. Yamamoto K, Ohishi M, Katsuya T, Ito N, Ikushima M, Kaibe M, Tatara Y, Shiota A, Sugano S, Takeda S, Rakugi H, Ogihara T. Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II. Hypertension. 2006;47:718–726. doi: 10.1161/01.HYP.0000205833.89478.5b.
    1. Ebermann L, Spillmann F, Sidiropoulos M, Escher F, Heringer-Walther S, Schultheiss HP, Tschöpe C, Walther T. The angiotensin-(1-7) receptor agonist AVE0991 is cardioprotective in diabetic rats. Eur J Pharmacol. 2008;590:276–280. doi: 10.1016/j.ejphar.2008.05.024.
    1. Gorelik G, Carbini LA, Scicli AG. Angiotensin-(1-7) induces bradykinin-mediated relaxation in porcine coronary artery. J Pharmacol Exp Ther. 1998;286:403–410.
    1. Deddish PA, Marcic B, Jackman HL, Wang H-Z, Skidgel RA, Erdos EG. N-domain–specific substrate and C-domain inhibitors of angiotensin-converting enzyme: angiotenisn-(1-7) and keto-ACE. Hypertension. 1998;31:912–917. doi: 10.1161/01.HYP.31.4.912.
    1. Minshall RD, Tan F, Nakamura F, Rabito SF, Becker RP, Marcic B, Erdös EG. Potentiation of the actions of bradykinin by angiotensin I-converting enzyme inhibitors. The role of expressed human bradykinin B2 receptors and angiotensin I-converting enzyme in CHO cells. Circ Res. 1997;81:848–856. doi: 10.1161/01.RES.81.5.848.
    1. Benzing T, Fleming I, Blaukat A, Muller-Esterl W, Busse R. Angiotensin-converting enzyme inhibitor ramiprilat interferes with the sequenstration of the B2 kinin receptor within the plasma membrane of native endothelial cells. Circulation. 1999;99:2034–2040. doi: 10.1161/01.CIR.99.15.2034.
    1. Danser AHJ, Tom B, de Vries R, Saxena PR. L-NAME-resistant bradykinin-induced relaxation in porcine coronary arteries is NO-dependent: effect of ACE inhibition. Br J Pharmacol. 2000;131:195–202. doi: 10.1038/sj.bjp.0703555.
    1. Ishiyama Y, Gallagher PE, Averill DB, Tallant EA, Brosnihan KB, Ferrario CM. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension. 2004;43:970–976. doi: 10.1161/01.HYP.0000124667.34652.1a.
    1. Agata J, Ura N, Yoshida H, Shinshi Y, Sasaki H, Hyakkoku M, Taniguchi S, Shimamoto K. Olmesartan is an angiotensin II receptor blocker with an inhibitory effect on angiotensin-converting enzyme. Hypertens Res. 2006;29:865–874. doi: 10.1291/hypres.29.865.
    1. Imai Y, Kuba K, Penninger JM. The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice. Exp Physiol. 2008;93:543–548. doi: 10.1113/expphysiol.2007.040048.
    1. Kuba K, Imai Y, Rao S, Jiang C, Penninger JM. Lessons from SARS: control of acute lung failure by the SARS receptor ACE2. J Mol Med. 2006;84:814–820. doi: 10.1007/s00109-006-0094-9.
    1. 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. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA. 2003;100:8258–8263. doi: 10.1073/pnas.1432869100.
    1. Santos RA, Ferreira AJ, E Silva AC. Recent advances in the angiotensin-converting enzyme 2-angiotensin(1-7)-Mas axis. Exp Physiol. 2008;93:519–527. doi: 10.1113/expphysiol.2008.042002.
    1. Villar AJ, Pedersen RA. Parental imprinting of the Mas protooncogene in mouse. Nature Genet. 1994;8:373–379. doi: 10.1038/ng1294-373.
    1. Metzger R, Bader M, Ludwig T, Berberich C, Bunnemann B, Ganten D. Expression of the mouse and rat mas proto-oncogene in the brain and peripheral tissues. FEBS Lett. 1995;357:27–32. doi: 10.1016/0014-5793(94)01292-9.
    1. Santos RA, Castro CH, Gava E, Pinheiro SV, Almeida AP, Paula RD, Cruz JS, Ramos AS, Rosa KT, Irigoyen MC, Bader M, Alenina N, Kitten GT, Ferreira AJ. Impairment of in vitro and in vivo heart function in angiotensin-(1-7) receptor MAS knockout mice. Hypertension. 2006;47:996–1002. doi: 10.1161/01.HYP.0000215289.51180.5c.
    1. Castro CH, Santos RA, Ferreira AJ, Bader M, Alenina N, Almeida AP. Effects of genetic deletion of angiotensin-(1-7) receptor Mas on cardiac function during ischemia/reperfusion in the isolated perfused mouse heart. Life Sci. 2006;80:264–268. doi: 10.1016/j.lfs.2006.09.007.
    1. 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–H1566. doi: 10.1152/ajpheart.00941.2004.

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