Angiotensin(1-7) Blunts Hypertensive Cardiac Remodeling by a Direct Effect on the Heart

Abstract

Abstract-Angiotensin-converting enzyme 2 (ACE2) converts the vasopressor angiotensin II (Ang II) into angiotensin (1)(2)(3)(4)(5)(6)(7) [Ang(1-7)], a peptide reported to have vasodilatory and cardioprotective properties. Inactivation of the ACE2 gene in mice has been reported by one group to result in an accumulation of Ang II in the heart and an age-related defect in cardiac contractility. A second study confirmed the role of ACE2 as an Ang II clearance enzyme but failed to reproduce the contractility defects previously reported in ACE2-deficient mice. The reasons for these differences are unclear but could include differences in the accumulation of Ang II or the deficiencies in Ang(1-7) in the mouse models used. As a result, the roles of ACE2, Ang II, and Ang(1-7) in the heart remain controversial. Using a novel strategy, we targeted the chronic overproduction of either Ang II or Ang(1-7) in the heart of transgenic mice and tested their effect on age-related contractility and on cardiac remodeling in response to a hypertensive challenge. We demonstrate that a chronic accumulation of Ang II in the heart does not result in cardiac contractility defects, even in older (8-month-old) mice. Likewise, transgenic animals with an 8-fold increase in Ang(1-7) peptide in the heart exhibited no differences in resting blood pressure or cardiac contractility as compared to age-matched controls, but they had significantly less ventricular hypertrophy and fibrosis than their nontransgenic littermates in response to a hypertensive challenge. Analysis of downstream signaling cascades demonstrates that cardiac Ang(1-7) selectively modulates some of the downstream signaling effectors of cardiac remodeling. These results suggest that Ang(1-7) can reduce hypertension-induced cardiac remodeling through a direct effect on the heart and raise the possibility that pathologies associated with ACE2 inactivation are mediated in part by a decrease in production of Ang(1-7).

Angiotensin-(1–7) Modulates Renal Vascular Resistance Through Inhibition of p38 Mitogen-Activated Protein Kinase in Apolipoprotein E–Deficient Mice

“…45 In addition, cardiac overexpression of Ang(1-7) improved Ang II-dependent cardiac hyper trophy by reducing p38 MAPK activity. 46 Therefore, we hypothesized that other mechanisms, independent from NO, might contribute to the attenuated pressor response to Ang II seen in Ang(1-7)-treated apoE(−/−) mice.…”

Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants

“…The recently discovered member of the RAS, ACE2, is an essential regulator of heart function (38) and has been used as a negative indicator of cardiovascular disease (CVD) due to its pivotal role in Ang (1-7) formation, implicated in several biological effects that are opposite to those elicited by Ang II, acting in anti-proliferation and vasodilator actions and anti-fibrosis effects (39,40). Higher cardiac Ang II levels were associated with genetic deletion of ACE2 in mice and resulted in the development of severe cardiac dysfunction (38).…”

Effects of Angiotensin Metabolites in the Coronary Vascular Bed of the Spontaneously Hypertensive Rat

“…18 Chronic treatment of apolipoprotein E knockout mice with Ang IV reversed vascular dysfunction, possibly by enhancing NO bioavailability in an AT 2 and/or Ang II type 4 receptor-dependent manner. 7 Finally, Ang-(1-7) exerts vasodepressor 19,20 and antiremodeling 21 effects under pathological conditions. Although this has been attributed to its capacity to activate Mas receptors, 22 it may also involve AT 2 receptor activation, 20 ACE inhibition, 23 and/or AT 1 receptor blockade.…”