Angiotensin Converting Enzyme 2 Suppresses Pathological Hypertrophy, Myocardial Fibrosis and Diastolic Dysfunction

Abstract

Background: Angiotensin-converting enzyme 2 (ACE2) is a pleiotropic monocarboxypeptidase capable of metabolizing several peptide substrates. We hypothesized that ACE2 is a negative regulator of angiotensin II (Ang II)-mediated signaling and its adverse effects on the cardiovascular system. Methods and Results: Ang II infusion (1.5 mg.kg−1.d−1) for 14 days resulted in worsening cardiac fibrosis and pathological hypertrophy in ACE2 knockout (Ace2-/y) mice compared to wildtype (WT) mice. Daily treatment of Ang II-infused WT mice with recombinant human ACE2 (rhACE2; 2 mg.kg−1.d−1; i.p.) blunted the hypertrophic response, expressions of hypertrophy markers and reduced the Ang II-induced superoxide production. Ang II-mediated myocardial fibrosis and expression of pro-collagen type Ia1, pro-collagen type IIIa1, TGFb1 and fibronectin were also suppressed by rhACE2. Ang II-induced diastolic dysfunction was normalized by rhACE2 in association with reduced plasma and myocardial Ang II and increased plasma Ang 1–7 levels. rhACE2 treatment reversed Ang II-mediated activation of protein kinase C (PKC)α and PKCβ1 protein levels and phosphorylation of the ERK1/2, JAK2 and STAT3 signaling pathways in WT mice. A subpressor dose of Ang II (0.15 mg.kg−1.d−1) resulted in a milder phenotype which was also completed suppressed by rhACE2 (2 mg.kg−1.d−1; i.p). In cultured adult murine ventricular cardiomyocytes and cardiofibroblasts, Ang II-mediated superoxide generation, collagen production and ERK1/2 signaling were suppressed by rhACE2 in an Ang 1–7 dependent manner. Importantly, rhACE2 partially prevented the development of dilated cardiomyopathy in pressure-overloaded wildtype mice. Conclusions: Elevated Ang II induces hypertension, myocardial hypertrophy, fibrosis and diastolic dysfunction which were exacerbated by ACE2 deficiency while rhACE2 prevents this Ang II-induced and pressure-overload induced myocardial adverse remodeling. Hence, ACE2 as an important negative regulator of Ang II-induced heart disease can have therapeutic potentials for patients with heart disease. Background: Angiotensin-converting enzyme 2 (ACE2) is a pleiotropic monocarboxypeptidase capable of metabolizing several peptide substrates. We hypothesized that ACE2 is a negative regulator of angiotensin II (Ang II)-mediated signaling and its adverse effects on the cardiovascular system. Methods and Results: Ang II infusion (1.5 mg.kg−1.d−1) for 14 days resulted in worsening cardiac fibrosis and pathological hypertrophy in ACE2 knockout (Ace2-/y) mice compared to wildtype (WT) mice. Daily treatment of Ang II-infused WT mice with recombinant human ACE2 (rhACE2; 2 mg.kg−1.d−1; i.p.) blunted the hypertrophic response, expressions of hypertrophy markers and reduced the Ang II-induced superoxide production. Ang II-mediated myocardial fibrosis and expression of pro-collagen type Ia1, pro-collagen type IIIa1, TGFb1 and fibronectin were also suppressed by rhACE2. Ang II-induced diastolic dysfunction was normalized by rhACE2 in association with reduced plasma and myocardial Ang II and increased plasma Ang 1–7 levels. rhACE2 treatment reversed Ang II-mediated activation of protein kinase C (PKC)α and PKCβ1 protein levels and phosphorylation of the ERK1/2, JAK2 and STAT3 signaling pathways in WT mice. A subpressor dose of Ang II (0.15 mg.kg−1.d−1) resulted in a milder phenotype which was also completed suppressed by rhACE2 (2 mg.kg−1.d−1; i.p). In cultured adult murine ventricular cardiomyocytes and cardiofibroblasts, Ang II-mediated superoxide generation, collagen production and ERK1/2 signaling were suppressed by rhACE2 in an Ang 1–7 dependent manner. Importantly, rhACE2 partially prevented the development of dilated cardiomyopathy in pressure-overloaded wildtype mice. Conclusions: Elevated Ang II induces hypertension, myocardial hypertrophy, fibrosis and diastolic dysfunction which were exacerbated by ACE2 deficiency while rhACE2 prevents this Ang II-induced and pressure-overload induced myocardial adverse remodeling. Hence, ACE2 as an important negative regulator of Ang II-induced heart disease can have therapeutic potentials for patients with heart disease.