Abstract 19679: Mitochondrial Aldehyde Dehydrogenase 2 (ALDH2) Ameliorates Angiotensin II-Induced Cardiac Remodeling and Myocardial Dysfunction through Inhibition of Mitochondrial Oxidative Stress and Induction of Autophagy

Abstract

Angiotensin II-induced cardiac damage is associated with oxidative stress, mitochondrial injury, cardiac remodeling and contractile dysfunction. ALDH2, a mitochondrial enzyme governing mitochondrial and cardiac function, displays distinct polymorphism and predisposes increased prevalence of hypertension. This study was designed to evaluate the role of ALDH2 in angiotensin II-induced myocardial remodeling and contractile dysfunction. Echocardiographic, cardiomyocyte contractile and intracellular Ca 2+ properties were examined in WT and ALDH2 transgenic mice with or without angiotensin II perfusion. Cardiac histology and autophagy, a process governing hypertrophy and oxidative stress, were evaluated. Myocardial contractile function and intracellular Ca 2+ handling were compromised in angiotensin II-perfused WT mice, the effects of which were significantly attenuated by ALDH2. H&E and Masson trichrome staining revealed cardiomyocyte hypertrophy and interstitial fibrosis associated with greater echocardiographic LV mass and wall thickness. ALDH2 ameliorated angiotensin II-induced cardiomyocyte hypertrophy, cardiac interstitial fibrosis, cardiomyocyte apoptosis, and cardiac atrial natriuretic peptide mRNA levels. The beneficial effect of ALDH2 was independent of blood pressure regulation and was linked to decreased ER stress, autophagy, and 5' AMP-activated protein kinase phosphorylation. Myocardial ER stress and autophagy were facilitated by angiotensin II associated with higher phosphorylation of AMPK. Mitochondria from angiotensin II perfused WT hearts showed clustered mitochondrial patterns, decreased numbers, and volume fractions but increased trans-sectional areas. All of these effects were reduced in ALDH2 mice. The ALDH2 activator Alda-1 ameliorated angiotensin II-induced mitochondrial injury and autophagy induction. Human study also revealed a positive correlation between high blood pressure prevalence and ALDH2 gene mutation. In summary, ALDH2 may provide a blood pressure-independent protection against angiotensin II-induced mitochondrial remodeling and cardiac contractile dysfunction, possibly through modulation of mitochondrial oxidative stress and autophagy induction.