Angiotensin-(1-7) significantly attenuated serum- or endothelin-1-stimulated protein synthesis and MAPK activity in cultured neonatal rat myocytes through activation of the mas receptor.
Does angiotensin-(1-7) reduce the growth of cardiac myocytes through activation of the mas receptor?
Angiotensin-(1-7) inhibits cardiomyocyte hypertrophy by attenuating protein synthesis and MAPK activation via the mas receptor, providing a mechanistic basis for the beneficial effects of ACE inhibitors and ARBs on cardiac remodeling.
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)Hleucine incorporation into myocytes with no effect on (3)Hthymidine 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.
Tallant et al. (Sat,) conducted a other in Myocyte hypertrophy and cardiac remodeling. Angiotensin-(1-7) vs. Control (fetal bovine serum or endothelin-1 stimulation without ANG-(1-7)) was evaluated on Protein and DNA synthesis ([(3)H]leucine and [(3)H]thymidine incorporation) and ERK1/ERK2 MAPK activity. Angiotensin-(1-7) significantly attenuated serum- or endothelin-1-stimulated protein synthesis and MAPK activity in cultured neonatal rat myocytes through activation of the mas receptor.