Angiotensin-(1–7) inhibits growth of cardiac myocytes through activation of themasreceptor

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, the selective ANG type 1-7 (AT1-7) receptor antagonist, blocked the ANG-(1-7)-mediated reduction in protein synthesis in cardiac myocytes, whereas the AT1 and AT2 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 ]-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 AT1 receptor blockers, ANG-(1-7) may contribute to their beneficial effects on cardiac dysfunction and ventricular remodeling after myocardial infarction. cardiac hypertrophy; mitogen-activated protein kinases [ANG-(1-7)] is an endogenous peptide hormone that produces unique physiological responses that are often opposite to those of the well-characterized angiotensin peptide ANG II (15). The ability of ANG II to increase blood pressure is documented; it is a potent vasoconstrictor, it stimulates thirst and aldosterone release, and inhibition of its production or effect with the use of angiotensin-converting enzyme (ACE) inhibitors or ANG type 1 (AT 1 ) receptor antagonists reduces mean arterial pressure (45). In addition, ANG II stimulates vascular growth as well as hypertrophy in terminally differentiated cells. In contrast, ANG-(1-7) reduces the blood pressure of hypertensive dogs and rats (4, 33), alters renal fluid absorption (11,19,22), causes vasodilation (6, 34, 35), and participates in the antihypertensive responses to ACE inhibition or AT 1 receptor blockade in hypertensive rats (24,25). In addition, we showed that ANG-(1-7) reduces vascular growth in vitro and in vivo (17,42,44), suggesting that ANG-(1-7) may act as an endogenous regulator of cell growth. Thus ANG-(1-7) opposes both the pressor and proliferative effects of ...

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

“…1] by our laboratory in 1988 (Schiavone et al 1988) and the cloning of ACE2 in 2000 (Donoghue et al 2000;Tipuis et al 2000) have led to a new perception of the intrinsic mechanisms through which the RAS regulates homeostasis. Ang-(1-7) is a downstream heptapeptide product of the system that can regulate blood pressure (Benter et al 1995b;Ferrario et al 2005), cardiac function (Ferreira et al 2002;Loot et al 2002;De Mello et al 2004), and cell growth (Tallant et al 2005).…”

“…It is well documented that Ang II promotes cell proliferation (Daemen et al 1991;Su et al 1998) and vasoconstriction (Wackenfors et al 2004), whereas Ang-(1-7) has antiproliferative actions on cardiac myocytes (Tallant et al 2005) and vascular smooth muscle (Strawn et al 1999), and is a vasodilator . These actions have uncovered a new way to think about the RAS, both conceptually and therapeutically.…”

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

“…[9][10][11] Moreover, it opposes the growth-stimulating effects of Ang II in vascular smooth muscle cells 12 and cardiomyocytes. 13 Ang-(1-7) also demonstrates effects on renal function by participating in the control of water and electrolyte homeostasis. 14 However, research involving Ang-(1-7) is not restricted to cardiovascular and renal function.…”

ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

“…Also in agreement with findings showing the cardioprotective effects of ANG-(1-7), a genetic deletion of the Mas receptor impaired heart function and changed the extracellular matrix to a profibrotic state [140]. After the activation of the Mas receptor, the intracellular signal transduction mechanisms that are involved in the following processes or tissues are poorly understood: i) in vivo, in the rat heart, ANG-(1-7) stimulated the phosphorylation of Janus kinase 2 (JAK2), insulin receptor substrate (IRS)-1 and Akt [141], ii) Mas receptor activation led to an increase in NO production via the phosphorylation of eNOS, a process that involves the activation of phosphatidylinositol 3-kinase-dependent Akt phosphorylation [142,143], and iii) upon the activation of the Mas receptor, MAPK phosphorylation is inhibited [144,145].…”