Angiotensin-Converting Enzyme 2 Suppresses Pathological Hypertrophy, Myocardial Fibrosis, and Cardiac 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 with wild-type (WT) mice. Daily treatment of Ang II–infused wild-type mice with recombinant human ACE2 (rhACE2; 2 mg · kg −1 · d −1 IP) blunted the hypertrophic response and expression of hypertrophy markers and reduced Ang II–induced superoxide production. Ang II–mediated myocardial fibrosis and expression of procollagen type Iα1, procollagen type IIIα1, transforming growth factor-β1, and fibronectin were also suppressed by rhACE2. Ang II–induced diastolic dysfunction was inhibited by rhACE2 in association with reduced plasma and myocardial Ang II and increased plasma Ang 1-7 levels. rhACE2 treatment inhibited Ang II–mediated activation of protein kinase C-α and protein kinase C-β1 protein levels and phosphorylation of the extracellular signal-regulated 1/2, Janus kinase 2, and signal transducer and activator of transcription 3 signaling pathways in wild-type mice. A subpressor dose of Ang II (0.15 mg · kg −1 · d −1 ) resulted in a milder phenotype that was strikingly attenuated by rhACE2 (2 mg · kg −1 · d −1 IP). In adult ventricular cardiomyocytes and cardiofibroblasts, Ang II–mediated superoxide generation, collagen production, and extracellular signal-regulated 1/2 signaling were inhibited by rhACE2 in an Ang 1-7–dependent manner. Importantly, rhACE2 partially prevented the development of dilated cardiomyopathy in pressure-overloaded wild-type mice. Conclusions— Elevated Ang II induced hypertension, myocardial hypertrophy, fibrosis, and diastolic dysfunction, which were exacerbated by ACE2 deficiency, whereas rhACE2 attenuated Ang II– and pressure-overload–induced adverse myocardial remodeling. Hence, ACE2 is an important negative regulator of Ang II–induced heart disease and suppresses adverse myocardial remodeling.