Targeting the ACE2-Ang-(1-7) pathway in cardiac fibroblasts to treat cardiac remodeling and heart failure

Journal of Molecular and Cellular Cardiology

Volumn 51, Issue 4, 2011, Pages 542-547

  Iwata, Michikado ^a   Cowling, Randy T ^a   Yeo, Seon Ju ^a   Greenberg, Barry ^a  

^a UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

Author keywords

ACE2; Angiotensin; Heart failure; Remodeling

Indexed keywords

ALDOSTERONE ANTAGONIST; ANGIOTENSIN CONVERTING ENZYME 2; ANGIOTENSIN II; ANGIOTENSIN[1-7]; CARDIOVASCULAR AGENT; CGEN 856S; COLLAGEN; MAS RECEPTOR; N ETHYLCARBAMOYL 3 [4 (5 FORMYL 4 METHOXY 2 PHENYL 1 IMIDAZOLYLMETHYL)PHENYL] 5 ISOBUTYL 2 THIOPHENESULFONAMIDE; RECEPTOR PROTEIN; TUMOR NECROSIS FACTOR ALPHA CONVERTING ENZYME; UNCLASSIFIED DRUG;

ATHEROSCLEROSIS; CARBOXY TERMINAL SEQUENCE; CARDIAC FIBROBLAST; COLLAGEN SYNTHESIS; EXTRACELLULAR MATRIX; FIBROBLAST; GENE EXPRESSION; HEART FAILURE; HEART INFARCTION; HEART MUSCLE CELL; HEART PROTECTION; HEART VENTRICLE HYPERTROPHY; HEART VENTRICLE REMODELING; HUMAN; NONHUMAN; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PROTEIN INTERACTION; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; TISSUE DISTRIBUTION;

ANGIOTENSIN I; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; ANIMALS; GENE EXPRESSION; HEART; HEART FAILURE; HUMANS; MOLECULAR TARGETED THERAPY; MYOCARDIUM; MYOFIBROBLASTS; ORGAN SPECIFICITY; PEPTIDE FRAGMENTS; PEPTIDYL-DIPEPTIDASE A; RENIN-ANGIOTENSIN SYSTEM; TRANSLATIONAL MEDICAL RESEARCH; VENTRICULAR REMODELING;

EID: 80052821710     PISSN: 00222828     EISSN: 10958584     Source Type: Journal    
DOI: 10.1016/j.yjmcc.2010.12.003     Document Type: Review

References (86)

1. Lloyd-Jones D.M., Larson M.G., Leip E.P., Beiser A., D'Agostino R.B., Kannel W.B., et al. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation 2002, 106:3068-3072.
2. Owan T.E., Hodge D.O., Herges R.M., Jacobsen S.J., Roger V.L., Redfield M.M. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006, 355:251-259.
3. Pfeffer M.A., Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation 1990, 81:1161-1172.
4. Sharpe N. Cardiac remodeling in congestive heart failure. congestive Heart Failure 2000, 101-115. Lippincott Williams & Wilkins, Philadelphia. Second ed. J.D. Hosenpud, B.H. Greenberg (Eds.).
5. Weber K.T., Sun Y. Remodeling of the Cardiac Interstitium in Ischemic Cardiomyopathy. Congestive Heart Failure 2000, 117-136. Lippincott Williams & Wilkins, Philadelphia. Second ed. J.D. Hosenpud, B.H. Greenberg (Eds.).
6. Beltrami C.A., Finato N., Rocco M., Feruglio G.A., Puricelli C., Cigola E., et al. Structural basis of end-stage failure in ischemic cardiomyopathy in humans. Circulation 1994, 89:151-163.
7. Brilla C.G., Scheer C., Rupp H. Renin-angiotensin system and myocardial collagen matrix: modulation of cardiac fibroblast function by angiotensin II type 1 receptor antagonism. J Hypertens Suppl 1997, 15:S13-S19.
8. Eghbali M., Blumenfeld O.O., Seifter S., Buttrick P.M., Leinwand L.A., Robinson T.F., et al. Localization of types I, III and IV collagen mRNAs in rat heart cells by in situ hybridization. J Mol Cell Cardiol 1989, 21:103-113.
9. Mann D.L., Spinale F.G. Activation of matrix metalloproteinases in the failing human heart: breaking the tie that binds. Circulation 1998, 98:1699-1702.
10. Sivasubramanian N., Coker M.L., Kurrelmeyer K.M., MacLellan W.R., DeMayo F.J., Spinale F.G., et al. Left ventricular remodeling in transgenic mice with cardiac restricted overexpression of tumor necrosis factor. Circulation 2001, 104:826-831.
11. Spinale F.G., Coker M.L., Krombach S.R., Mukherjee R., Hallak H., Houck W.V., et al. Matrix metalloproteinase inhibition during the development of congestive heart failure: effects on left ventricular dimensions and function. Circ Res 1999, 85:364-376.
12. Gray M.O., Long C.S., Kalinyak J.E., Li H.T., Karliner J.S. Angiotensin II stimulates cardiac myocyte hypertrophy via paracrine release of TGF-beta 1 and endothelin-1 from fibroblasts. Cardiovasc Res 1998, 40:352-363.
13. Harada M., Itoh H., Nakagawa O., Ogawa Y., Miyamoto Y., Kuwahara K., et al. Significance of ventricular myocytes and nonmyocytes interaction during cardiocyte hypertrophy: evidence for endothelin-1 as a paracrine hypertrophic factor from cardiac nonmyocytes. Circulation 1997, 96:3737-3744.
14. Ito H., Hirata Y., Adachi S., Tanaka M., Tsujino M., Koike A., et al. Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest 1993, 92:398-403.
15. Iwata M., Cowling R.T., Gurantz D., Moore C., Zhang S., Yuan J.X., 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-H2363.
16. Dostal D.E., Baker K.M. The cardiac renin-angiotensin system: conceptual, or a regulator of cardiac function?. Circ Res 1999, 85:643-650.
17. Villarreal F.J., Kim N.N., Ungab G.D., Printz M.P., Dillmann W.H. Identification of functional angiotensin II receptors on rat cardiac fibroblasts. Circulation 1993, 88:2849-2861.
18. Kim S., Ohta K., Hamaguchi A., Yukimura T., Miura K., Iwao H. Angiotensin II induces cardiac phenotypic modulation and remodeling in vivo in rats. Hypertension 1995, 25:1252-1259.
19. Gurantz D., Cowling R.T., Varki N., Frikovsky E., Moore C.D., Greenberg B.H. IL-1beta and TNF-alpha upregulate angiotensin II type 1 (AT1) receptors on cardiac fibroblasts and are associated with increased AT1 density in the post-MI heart. J Mol Cell Cardiol 2005, 38:505-515.
20. Lefroy D.C., Wharton J., Crake T., Knock G.A., Rutherford R.A., Suzuki T., et al. Regional changes in angiotensin II receptor density after experimental myocardial infarction. J Mol Cell Cardiol 1996, 28:429-440.
21. Muller D.N., Fischli W., Clozel J.P., Hilgers K.F., Bohlender J., Menard J., et al. Local angiotensin II generation in the rat heart: role of renin uptake. Circ Res 1998, 82:13-20.
22. Pfeffer M.A., Braunwald E., Moye L.A., Basta L., Brown E.J., Cuddy T.E., et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 1992, 327:669-677.
23. Harada K., Sugaya T., Murakami K., Yazaki Y., Komuro I. Angiotensin II type 1A receptor knockout mice display less left ventricular remodeling and improved survival after myocardial infarction. Circulation 1999, 100:2093-2099.
24. Greenberg B., Quinones M.A., Koilpillai C., Limacher M., Shindler D., Benedict C., et al. Effects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Results of the SOLVD echocardiography substudy. Circulation 1995, 91:2573-2581.
25. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med 1991, 325:293-302.
26. Maggioni A.P., Anand I., Gottlieb S.O., Latini R., Tognoni G., Cohn J.N. Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 2002, 40:1414-1421.
27. Granger C.B., McMurray J.J., Yusuf S., Held P., Michelson E.L., Olofsson B., et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003, 362:772-776.
28. Tipnis S.R., Hooper N.M., Hyde R., Karran E., Christie G., Turner A.J. A human homolog of angiotensin-converting enzyme - cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 2000, 275:33238-33243.
29. Donoghue M., Hsieh F., Baronas E., Godbout K., Gosselin M., Stagliano N., et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 2000, 87:E1-E9.
30. Vickers C., Hales P., Kaushik V., Dick L., Gavin J., Tang J., et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 2002, 277:14838-14843.
31. Lara Lda S., Cavalcante F., Axelband F., De Souza A., Lopes A., Caruso-Neves C. Involvement of the Gi/o/cGMP/PKG pathway in the AT2-mediated inhibition of outer cortex proximal tubule Na+-ATPase by Ang-(1-7). Biochem J 2006, 395:183-190.
32. Lara L.S., Correa J.S., Lavelle A.B., Lopes A.G., Caruso-Neves C. The angiotensin receptor type 1-Gq protein-phosphatidyl inositol phospholipase Cbeta-protein kinase C pathway is involved in activation of proximal tubule Na+-ATPase activity by angiotensin(1-7) in pig kidneys. Exp Physiol 2008, 93:639-647.
33. Lopez Verrilli M.A., Pirola C.J., Pascual M.M., Dominici F.P., Turyn D., Gironacci M.M. Angiotensin-(1-7) through AT receptors mediates tyrosine hydroxylase degradation via the ubiquitin-proteasome pathway. J Neurochem 2009, 109:326-335.
34. Santos R.A.S., Silva A.C.S.E., Maric C., Silva D.M.R., Machado R.P., de Buhr I., et al. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA 2003, 100:8258-8263.
35. Kostenis E., Milligan G., Christopoulos A., Sanchez-Ferrer C.F., Heringer-Walther S., Sexton P.M., et al. G-protein-coupled receptor Mas is a physiological antagonist of the angiotensin II type 1 receptor. Circulation 2005, 111:1806-1813.
36. Gembardt F., Sterner-Kock A., Imboden H., Spalteholz M., Reibitz F., Schultheiss H.P., et al. Organ-specific distribution of ACE2 mRNA and correlating peptidase activity in rodents. Peptides 2005, 26:1270-1277.
37. Burrell L.M., Risvanis J., Kubota E., Dean R.G., MacDonald P.S., Lu S., et al. Myocardial infarction increases ACE2 expression in rat and humans. Eur Heart J 2005, 26:369-375.
38. Guy J.L., Lambert D.W., Turner A.J., Porter K.E. Functional angiotensin-converting enzyme 2 is expressed in human cardiac myofibroblasts. Exp Physiol 2008, 93:579-588.
39. Ishiyama Y., Gallagher P.E., Averill D.B., Tallant E.A., Brosnihan K.B., Ferrario C.M. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension 2004, 43:970-976.
40. Ocaranza M.P., Godoy I., Jalil J.E., Varas M., Collantes P., Pinto M., et al. Enalapril attenuates downregulation of Angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat. Hypertension 2006, 48:572-578.
41. Karram T., Abbasi A., Keidar S., Golomb E., Hochberg I., Winaver J., et al. Effects of spironolactone and eprosartan on cardiac remodeling and angiotensin-converting enzyme isoforms in rats with experimental heart failure. Am J Physiol Heart Circ Physiol 2005, 289:H1351-H1358.
42. Lambert D.W., Yarski M., Warner F.J., Thornhill P., Parkin E.T., Smith A.I., 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, 280:30113-30119.
43. Iwata M., Silva Enciso J.E., Greenberg B.H. Selective 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-C1329.
44. Epelman S., Tang W.H., Chen S.Y., Van L.F., Francis G.S., Sen S. Detection of soluble angiotensin-converting enzyme 2 in heart failure: insights into the endogenous counter-regulatory pathway of the renin-angiotensin-aldosterone system. J Am Coll Cardiol 2008, 52:750-754.
45. Martin K.A., Grant S.G., Hockfield S. The mas proto-oncogene is developmentally regulated in the rat central nervous system. Brain Res Dev Brain Res 1992, 68:75-82.
46. Kitaoka T., Sharif M., Hanley M.R., Hjelmeland L.M. Expression of the MAS proto-oncogene in the retinal pigment epithelium of the rhesus macaque. Curr Eye Res 1994, 13:345-351.
47. 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.
48. Munoz M.C., Giani J.F., Dominici F.P. Angiotensin-(1-7) stimulates the phosphorylation of Akt in rat extracardiac tissues in vivo via receptor Mas. Regul Pept 2010, 161:1-7.
49. Alenina N., Xu P., Rentzsch B., Patkin E.L., Bader M. Genetically altered animal models for Mas and angiotensin-(1-7). Exp Physiol 2008, 93:528-537.
50. Dias-Peixoto M.F., Santos R.A., Gomes E.R., Alves M.N., Almeida P.W., Greco L., et al. Molecular mechanisms involved in the angiotensin-(1-7)/Mas signaling pathway in cardiomyocytes. Hypertension 2008, 52:542-548.
51. Tallant E.A., Ferrario C.M., Gallagher P.E. Angiotensin-(1-7) inhibits growth of cardiac myocytes through activation of the mas receptor. Am J Physiol Heart Circ Physiol 2005, 289:H1560-H1566.
52. Crackower M.A., Sarao R., Oudit G.Y., Yagil C., Kozieradzki I., Scanga S.E., et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 2002, 417:822-828.
53. Gurley S.B., Allred A., Le T.H., Griffiths R., Mao L., Philip N., et al. Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice. J Clin Invest 2006, 116:2218-2225.
54. Yamamoto K., Ohishi M., Katsuya T., Ito N., Ikushima M., Kaibe M., et al. Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II. Hypertension 2006, 47:718-726.
55. Huentelman M.J., Grobe J.L., Vazquez J., Stewart J.M., Mecca A.P., Katovich M.J., et al. Protection from angiotensin II-induced cardiac hypertrophy and fibrosis by systemic lentiviral delivery of ACE2 in rats. Exp Physiol 2005, 90:783-790.
56. ez-Freire C., Vazquez J., Correa de Adjounian M.F., Ferrari M.F., Yuan L., Silver X., et al. ACE2 gene transfer attenuates hypertension-linked pathophysiological changes in the SHR. Physiol Genomics 2006, 27:12-19.
57. Der Sarkissian S., Grobe J.L., Yuan L., Narielwala D.R., Walter G.A., Katovich M.J., et al. Cardiac overexpression of angiotensin converting enzyme 2 protects the heart from ischemia-induced pathophysiology. Hypertension 2008, 51:712-718.
58. Kim M.A., Yang D., Kida K., Molotkova N., Yeo S.J., Varki N., et al. Effects of ACE2 inhibition in the post-myocardial infarction heart. J Card Fail 2010, 16:777-785.
59. Donoghue M., Wakimoto H., Maguire C.T., Acton S., Hales P., Stagliano N., et al. Heart block, ventricular tachycardia, and sudden death in ACE2 transgenic mice with downregulated connexins. J Mol Cell Cardiol 2003, 35:1043-1053.
60. Masson R., Nicklin S.A., Craig M.A., McBride M., Gilday K., Gregorevic P., et al. Onset of experimental severe cardiac fibrosis is mediated by overexpression of Angiotensin-converting enzyme 2. Hypertension 2009, 53:694-700.
61. Ferrario C.M., Jessup J., Chappell M.C., Averill D.B., Brosnihan K.B., Tallant E.A., et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 2005, 111:2605-2610.
62. Keidar S., Gamliel-Lazarovich A., Kaplan M., Pavlotzky E., Hamoud S., Hayek T., et al. Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients. Circ Res 2005, 97:946-953.
63. Zohn I.E., Symons M., Chrzanowska-Wodnicka M., Westwick J.K., Der C.J. Mas oncogene signaling and transformation require the small GTP-binding protein Rac. Mol Cell Biol 1998, 18:1225-1235.
64. Canals M., Jenkins L., Kellett E., Milligan G. Up-regulation of the angiotensin II type 1 receptor by the MAS proto-oncogene is due to constitutive activation of Gq/G11 by MAS. J Biol Chem 2006, 281:16757-16767.
65. Gembardt F., Grajewski S., Vahl M., Schultheiss H.P., Walther T. Angiotensin metabolites can stimulate receptors of the Mas-related genes family. Mol Cell Biochem 2008, 319:115-123.
66. Fraga-Silva R.A., Pinheiro S.V., Goncalves A.C., Alenina N., Bader M., Santos R.A. The antithrombotic effect of angiotensin-(1-7) involves mas-mediated NO release from platelets. Mol Med 2008, 14:28-35.
67. Sampaio W.O., Souza dos Santos R.A., Faria-Silva R., da Mata Machado L.T., Schiffrin E.L., Touyz R.M. Angiotensin-(1-7) through receptor Mas mediates endothelial nitric oxide synthase activation via Akt-dependent pathways. Hypertension 2007, 49:185-192.
68. Lin C.S., Pan C.H., Wen C.H., Yang T.H., Kuan T.C. Regulation of angiotensin converting enzyme II by angiotensin peptides in human cardiofibroblasts. Peptides 2010, 31:1334-1340.
69. Gava E., Samad-Zadeh A., Zimpelmann J., Bahramifarid N., Kitten G.T., Santos R.A., et al. Angiotensin-(1-7) activates a tyrosine phosphatase and inhibits glucose-induced signalling in proximal tubular cells. Nephrol Dial Transplant 2009, 24:1766-1773.
70. Peiro C., Vallejo S., Gembardt F., Azcutia V., Heringer-Walther S., Rodriguez-Manas L., et al. Endothelial dysfunction through genetic deletion or inhibition of the G protein-coupled receptor Mas: a new target to improve endothelial function. J Hypertens 2007, 25:2421-2425.
71. Zisman L.S., Keller R.S., Weaver B., Lin Q., Speth R., Bristow M.R., et al. Increased angiotensin-(1-7)-forming activity in failing human heart ventricles: evidence for upregulation of the angiotensin-converting enzyme homologue ACE2. Circulation 2003, 108:1707-1712.
72. Goulter A.B., Goddard M.J., Allen J.C., Clark K.L. ACE2 gene expression is up-regulated in the human failing heart. BMC Med 2004, 2:19.
73. Lew R.A., Warner F.J., Hanchapola I., Yarski M.A., Manohar J., Burrell L.M., et al. Angiotensin-converting enzyme 2 catalytic activity in human plasma is masked by an endogenous inhibitor. Exp Physiol 2008, 93:685-693.
74. Takahashi Y., Haga S., Ishizaka Y., Mimori A. Autoantibodies to angiotensin-converting enzyme 2 in patients with connective tissue diseases. Arthritis Res Ther 2010, 12:R85.
75. Hernandez Prada J.A., Ferreira A.J., Katovich M.J., Shenoy V., Qi Y., Santos R.A., et al. Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents. Hypertension 2008, 51:1312-1317.
76. Wysocki J., Ye M., Rodriguez E., Gonzalez-Pacheco F.R., Barrios C., Evora K., et al. Targeting the degradation of angiotensin II with recombinant angiotensin-converting enzyme 2: prevention of angiotensin II-dependent hypertension. Hypertension 2010, 55:90-98.
77. Oudit G.Y., Liu G.C., Zhong J., Basu R., Chow F.L., Zhou J., et al. Human recombinant ACE2 reduces the progression of diabetic nephropathy. Diabetes 2010, 59:529-538.
78. Loot A.E., Roks A.J., Henning R.H., Tio R.A., Suurmeijer A.J., Boomsma F., et al. Angiotensin-(1-7) attenuates the development of heart failure after myocardial infarction in rats. Circulation 2002, 105:1548-1550.
79. Langeveld B., van Gilst W.H., Tio R.A., Zijlstra F., Roks A.J. Angiotensin-(1-7) attenuates neointimal formation after stent implantation in the rat. Hypertension 2005, 45:138-141.
80. Benter I.F., Yousif M.H., Cojocel C., Al-Maghrebi M., Diz D.I. Angiotensin-(1-7) prevents diabetes-induced cardiovascular dysfunction. Am J Physiol Heart Circ Physiol 2007, 292:H666-H672.
81. Ebermann L., Spillmann F., Sidiropoulos M., Escher F., Heringer-Walther S., Schultheiss H.P., et al. The angiotensin-(1-7) receptor agonist AVE0991 is cardioprotective in diabetic rats. Eur J Pharmacol 2008, 590:276-280.
82. Ferreira A.J., Oliveira T.L., Castro M.C., Almeida A.P., Castro C.H., Caliari M.V., et al. Isoproterenol-induced impairment of heart function and remodeling are attenuated by the nonpeptide angiotensin-(1-7) analogue AVE 0991. Life Sci 2007, 81:916-923.
83. Ferreira A.J., Jacoby B.A., Araujo C.A., Macedo F.A., Silva G.A., Almeida A.P., 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-H1119.
84. Toton-Zuranska J., Gajda M., Pyka-Fosciak G., Kus K., Pawlowska M., Niepsuj A., et al. AVE 0991-angiotensin-(1-7) receptor agonist, inhibits atherogenesis in apoE-knockout mice. J Physiol Pharmacol 2010, 61:181-183.
85. Savergnini S.Q., Beiman M., Lautner R.Q., de Paula-Carvalho V., Allahdadi K., Pessoa D.C., et al. Vascular relaxation, antihypertensive effect, and cardioprotection of a novel peptide agonist of the MAS receptor. Hypertension 2010, 56:112-120.
86. Bikkavilli R.K., Tsang S.Y., Tang W.M., Sun J.X., Ngai S.M., Lee S.S., et al. Identification and characterization of surrogate peptide ligand for orphan G protein-coupled receptor mas using phage-displayed peptide library. Biochem Pharmacol 2006, 71:319-337.