Abstract 68: Diminazene, an Angiotensin Converting Enzyme2 (ACE2) Activator, Improves Right Heart Function in Experimental Models of Pressure Overload

Abstract

BACKGROUND: Right ventricular (RV) failure due to pressure overload is a major cause of morbidity and mortality in pulmonary hypertensive patients. We and others have shown that ACE2 exerts cardiopulmonary protection against lung diseases. This has led us to hypothesize that activation of ACE2 would improve RV hemodynamics and attenuate cardiac remodeling in animal models of pressure-overload. Methods: Hypoxia and Monocrotaline (MCT) models of pressure-overload were employed to evaluate the effects of Diminazene (DIZE), an ACE2 activator. Rats were exposed to hypoxia for 28 days with simultaneous DIZE treatment (15mg/Kg). In the other model, rats were challenged with MCT (50mg/Kg).Both prevention and reversal protocols were studied in this model. In the prevention protocol, rats were co-treated with DIZE for 4-weeks, while for the reversal protocol, DIZE was injected after 3-weeks of MCT-challenge and the drug treatment continued for additional 2-weeks. Results: Hypoxia exposed rats exhibited increased ratio of right ventricular to left ventricular plus septum weights, an index of RV hypertrophy (Con:0.26+0.01; Hypoxia: 0.48+0.03), along with cardiac dysfunction in terms of higher right ventricular end diastolic pressure (RVEDP; Con:3.28+0.65; Hypoxia:9.08+0.72mmHg), elevated +dP/dt (Con:2039+230; Hypoxia:2815+156mmHg/s) and increased -dP/dt (Con:-1476+98; Hypoxia:-2663+150mmHg/s). However, DIZE improved all these cardiovascular alterations (RVH:0.38+0.01; RVEDP:7.03+0.3mmHg; +dP/dt:2086+137mmHg/s;-dP/dt: -1945+100mmHg/s). Likewise, MCT injection induced RV hypertrophy (Con:0.27+0.01; MCT:0.50+0.03) and cardiac dysfunction (RVEDP; Con:3.98+0.46; MCT: 8.54+0.56mmHg; +dP/dt; Con:2107+189; MCT:3718+222mmHg/s; -dP/dt; Con:-1545+95; MCT:-2918+238mmHg/s), which was prevented by DIZE (RVH:0.29+0.02; RVEDP:4.76+0.44mmHg; +dP/dt:2525+122mmHg/s; -dP/dt:-2076+150mmHg/s). Furthermore, MCT caused a 3-fold increase in myocardial fibrosis, which was reduced by DIZE. In the reversal protocol, DIZE attenuated RV hypertrophy and improved cardiac hemodynamics. CONCLUSIONS: Collectively, our results identify a therapeutic potential of DIZE for RV dysfunction induced by pulmonary pressure-overload.