Prevention of angiotensin II-induced cardiac remodeling by angiotensin-(1–7)

Abstract

Cardiac remodeling, which typically results from chronic hypertension or following an acute myocardial infarction, is a major risk factor for the development of heart failure and, ultimately, death. The renin-angiotensin system (RAS) has previously been established to play an important role in the progression of cardiac remodeling, and inhibition of a hyperactive RAS provides protection from cardiac remodeling and subsequent heart failure. Our previous studies have demonstrated that overexpression of angiotensin-converting enzyme 2 (ACE2) prevents cardiac remodeling and hypertrophy during chronic infusion of angiotensin II (ANG II). This, coupled with the knowledge that ACE2 is a key enzyme in the formation of ANG-(1-7), led us to hypothesize that chronic infusion of ANG-(1-7) would prevent cardiac remodeling induced by chronic infusion of ANG II. Infusion of ANG II into adult Sprague-Dawley rats resulted in significantly increased blood pressure, myocyte hypertrophy, and midmyocardial interstitial fibrosis. Coinfusion of ANG-(1-7) resulted in significant attenuations of myocyte hypertrophy and interstitial fibrosis, without significant effects on blood pressure. In a subgroup of animals also administered [d-Ala(7)]-ANG-(1-7) (A779), an antagonist to the reported receptor for ANG-(1-7), there was a tendency to attenuate the antiremodeling effects of ANG-(1-7). Chronic infusion of ANG II, with or without coinfusion of ANG-(1-7), had no effect on ANG II type 1 or type 2 receptor binding in cardiac tissue. Together, these findings indicate an antiremodeling role for ANG-(1-7) in cardiac tissue, which is not mediated through modulation of blood pressure or altered cardiac angiotensin receptor populations and may be at least partially mediated through an ANG-(1-7) receptor.

Characterization of angiotensin-converting enzymes 1 and 2 in the soleus and plantaris muscles of rats

“…Studies have proposed that ACE2 might protect against CVD by diminishing Ang II concentration, consequently resulting in augmented Ang-(1-7) generation (19). This implies that there is a balance between ACE1 and ACE2 in the control of the Ang II and Ang-(1-7) levels.…”

Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

“…Ang-(1-7) also attenuated either fetal bovine serum-or endothelin 1-stimulated 3 H-leucine incorporation into isolated neonatal rat cardiac myocytes through a mechanism involving inhibition of serum-stimulated ERK1/2 MAP kinase activity and activation of Mas (Tallant et al 2005). Chronic administration of this peptide significantly attenuated left ventricular hypertrophy and fibrosis in pressure-overloaded rats (Wang et al 2005) and fibrosis in Ang II-infused and deoxycorticosterone acetate (DOCA)-salt rats (Grobe et al , 2007. Importantly, deletion of Mas produced impairment of cardiac function associated with a significant increase in collagen type I, III and fibronectin content in the heart (Santos et al 2006, Gava et al 2012.…”

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

“…Indeed, chronic Ang-(1-7) treatment not only attenuated the development of heart failure in response to coronary artery ligation in rats (Loot et al 2002), but it also reversed cardiac hypertrophy and fibrosis in rats (Iwata et al 2005;Tallant et al 2005;Wang et al 2005;Grobe et al 2006a;2006b). Ishiyama et al (2004) found that heart failure induced by coronary artery ligation was associated with an increase in plasma Ang-(1-7) levels, which was augmented with the administration of the AT 1 receptor blockers losartan and olmesartan.…”