Abstract P120: Effect Of Alamandine On Isoproterenol-induced Left Ventricular Dysfunction, Cardiac Remodeling And Immune Responses In Rat

Abstract

Alamandine, a newly identified derivative of angiotensin II has been shown to exert antihypertensive and vasodilative actions, and may represent a novel component of cardioprotective axis of renin angiotensin system. We sought to determine the protective effects of alamandine on isoproterenol (ISO) induced cardiac remodeling and dysfunction in rats. Male SD rats (n=6 in each group) received a two-week subcutaneous infusion of vehicle, ISO (10 mg/kg/day) or a combination of ISO and alamandine (50 ng/kg/min). Compared with vehicle group, the ratio of heart/body weight (mg/g) in ISO treated rats was significantly (*P<0.05) elevated (3.93 ± 0.18 vs. 3.07 ± 0.08*), which was markedly attenuated by alamandine (3.50 ± 0.08*). Echocardiographic assessment showed that alamandine improved ISO-induced left ventricular (LV) dysfunction evidenced by reducing LV thickness (1.68 ± 0.07* vs 1.90 ± 0.02 mm), end diastolic and systolic volume. Rats treated with alamandine had reduced E/E' ratio (15.16 ± 1.04* vs 26.81 ± 3.79) and increased E'/A' ratio (1.09 ± 0.05 vs 0.57 ± 0.07 ** P<0.01), indicating the improved diastolic cardiac function. The reduced myocardial performance index (0.74 ± 0.06* vs. 1.24 ± 0.15) in alamandine treated rats demonstrated an improvement of global cardiac dysfunction. Histological analysis also revealed that alamandine attenuated ISO induced increase in cardiomyocyte size (372.46 ± 11.13** vs 551.99 ± 11.79 μm 2 ) and myocardial fibrosis (1.39 ± 0.16 ** vs 4.57 ± 0.35), along with reduced mRNA expression of hypertrophy biomarkers atrial natriuretic peptide (2.45 ± 0.71** vs 8.08 ± 0.74), brain natriuretic peptide (2.86 ± 0.35 ** vs 12.53 ± 1.12), beta myosin heavy chain (1.71 ± 0.25* vs 5.38 ± 0.95) and fibrosis genes – collagen-1 (1.97 ± 0.45* vs 4.25 ± 0.6), fibronectin (2.04 ± 0.32** vs 5.05 ± 0.74), α-smooth muscle actin (1.53 ± 0.1** vs 2.71 ± 0.17). Flow cytometry analysis unveiled that alamandine reduced neutrophil, CD8 T cells and M1 monocytes, but increased M2 monocytes of left ventricle, implying the reduction of inflammation of the heart. These data suggest that alamandine plays a cardioprotective role in improving cardiac hypertrophy and fibrosis, probably via an immune mechanism to alleviate inflammatory responses during cardiac remodeling.