Small molecule ACE2 activator, Diminazene aceturate (DIZE) attenuates MI‐induced cardiac pathophysiology

Angiotensin‐converting enzyme 2 (ACE2) plays a critical role in maintaining cardiac homoeostasis during myocardial infarction (MI). We hypothesize that DIZE would produce beneficial outcomes in the cardiac pathophysiology induced by ischemia. DIZE treatment (15 mg/kg/day, s.c.) was initiated two days before MI surgery and continued throughout the study. MI rats showed a significant decrease in fractional shortening (FS, %) (control: 54.2 ± 2.6; DIZE alone: 52.5±2.9; MI: 32.3±2.3), increases in left ventricular end diastolic pressure (LVEDP, mmHg) (control: 3.0±0.7; DIZE alone: 2.6 ±0.8; MI: 14.2±2.6) and ventricular hypertrophy (VH, mg/mm tibia length) (control: 26.5±1.5; DIZE alone: 26.9 ± 1.4; MI: 33.4± 1.1). DIZE treatment significantly prevented each of these impairments in the MI rats (FS 44.29 ± 1.55 %, LVEDP 5.7 ± 2.8 mmHg, VH 26.5 ± 0.7 mg/mm). DIZE treatment also resulted in a significant increase in the cardiac ACE2 activity and its mRNA levels while AT1R and ACE mRNA levels were decreased. DIZE treatment caused an increase in cardiac progenitor cells and prevented the infiltration of macrophages into the peri‐infarct area of the ischemic heart. Collectively, our observations indicate that activation of endogenous ACE2 improves cardiac function and attenuates left ventricular remodeling post‐MI. Thus, DIZE treatment may represent a promising therapeutic strategy for MI.