title: Angiotensin-(1-7) inhibits growth of cardiac myocytes through activation of the mas receptor.
abstract: Peptide hormones such as ANG II and endothelin contribute to cardiac remodeling after myocardial infarction by stimulating myocyte hypertrophy and myofibroblast proliferation. In contrast, angiotensin-(1-7) [ANG-(1-7)] infusion after myocardial infarction reduced myocyte size and attenuated ventricular dysfunction and remodeling. We measured the effect of ANG-(1-7) on protein and DNA synthesis in cultured neonatal rat myocytes to assess the role of the heptapeptide in cell growth. ANG-(1-7) significantly attenuated either fetal bovine serum- or endothelin-1-stimulated [(3)H]leucine incorporation into myocytes with no effect on [(3)H]thymidine incorporation. [d-Ala(7)]-ANG-(1-7), the selective ANG type 1-7 (AT(1-7)) receptor antagonist, blocked the ANG-(1-7)-mediated reduction in protein synthesis in cardiac myocytes, whereas the AT(1) and AT(2) angiotensin peptide receptors were ineffective. Serum-stimulated ERK1/ERK2 mitogen-activated protein kinase activity was significantly decreased by ANG-(1-7) in myocytes, a response that was also blocked by [d-Ala(7)]-ANG-(1-7). Both rat heart and cardiac myocytes express the mRNA for the mas receptor, and a 59-kDa immunoreactive protein was identified in both extracts of rat heart and cultured myocytes by Western blot hybridization with the use of an antibody to mas, an ANG-(1-7) receptor. Transfection of cultured myocytes with an antisense oligonucleotide to the mas receptor blocked the ANG-(1-7)-mediated inhibition of serum-stimulated MAPK activation, whereas a sense oligonucleotide was ineffective. These results suggest that ANG-(1-7) reduces the growth of cardiomyocytes through activation of the mas receptor. Because ANG-(1-7) is elevated after treatment with angiotensin-converting enzyme inhibitors or AT(1) receptor blockers, ANG-(1-7) may contribute to their beneficial effects on cardiac dysfunction and ventricular remodeling after myocardial infarction.
authors.affiliation: Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1032, USA. atallant@wfubmc.edu
authors.forename: E Ann
authors.initials: EA
authors.lastname: Tallant
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Ferrario
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Gallagher
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D000959:Antihypertensive Agents; D016376:Oligonucleotides, Antisense; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D000803:Angiotensin I; C118790:angiotensin I (1-7)