Prevention of angiotensin II-induced hypertension and cardiac remodeling by recombinant human angiotensin-converting enzyme 2 in mice

Abstract

Objectives Overactivity of renin–angiotensin system (RAS) leading to increased levels of angiotensin (Ang) II is associated with hypertension and myocardial remodeling. Ang-converting enzyme 2 (ACE2) was recently identified as Ang II-degrading enzyme capable of generating Ang-(1–7). We hypothesized that ACE2 mediates its anti-hypertensive and anti-remodeling effects through the modulation of Ang II signaling. Design and methods The mini-osmotic pumps were implanted with Ang II (1.5 mg/kg/day) for 14 days in male ACE2 mutant (Ace2−/y) and wildtype (WT, Ace2+/y) mice. Ang II-infused WT mice were then treated with recombinant human ACE2 (rhACE2; 2 mg/kg daily i.p.) or placebo. We characterized the functional, structural and molecular changes in the heart in response to rhACE2. Results Chronic Ang II infusion resulted in an enhanced systolic blood pressure (166±5 mmHg, n=9, p<0.01), treatment with rhACE2 reduced the pressor response (139±6 mmHg; n=6, p<0.05) and blunted the hypertrophic response based on left ventricular mass and mRNA expressions of brain natriuretic peptide and α-skeletal actin. Interestingly, echocardiographic assessment revealed attenuated ventricular remodeling and improvement in diastolic dysfunction in Ang II-infused mice injected with rhACE2. Western blot exhibited a marked reversal of Ang II-mediated phosphorylation of Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) (n=4, p<0.05) in WT mice treated with rhACE2. In Ace2−/y mice, Ang II infusion resulted in greater pressor response (187±8 mmHg; n=10, p<0.01) and worsened cardiac remodeling and dysfunction compared to WT mice infused with Ang II. Conclusions Recombinant human ACE2 prevents Ang II-induced hypertension and myocardial remodeling while ACE2 deficiency worsens Ang II-induced hypertension and cardiac dysfunction. ACE2 may provide a novel therapeutic approach for patients with hypertension and cardiovascular diseases.