Abstract 9508: The Natural Product Zerumbone Suppresses Pressure Overload-Induced Cardiac Dysfunction by Inhibiting Cardiac Hypertrophy and Fibrosis

Abstract

Introduction: Cardiac hypertrophy and fibrosis are hallmarks of cardiac remodeling and are involved functionally in the development of heart failure (HF). Various food components effectively prevent cardiovascular diseases. However, it is unknown whether zerumbone (ZER), a major active terpene found in endemic wild ginger species, suppresses cardiac hypertrophy, fibrosis, and dysfunction. Hypothesis: We assessed the hypothesis that ZER suppresses cardiac hypertrophy and fibrosis in vitro and in vivo . Methods: The effects of ZER on phenylephrine (PE)-induced hypertrophic responses and on transforming growth factor beta (TGF-β)-induced fibrotic responses were examined in primary cultured cardiomyocytes and fibroblasts from neonatal rats. To determine whether ZER prevents the development of pressure overload-induced HF in vivo , a transverse aortic constriction mouse model was utilized (n=6-10). One day after surgery, mice were randomly divided into two groups and orally administered with ZER 20 mg / kg or vehicle for 8 weeks. Cardiac function was evaluated by echocardiography. Changes in cardiomyocyte surface area and degree of fibrosis were observed by histological analysis (HE and WGA staining). The total mRNA levels of the genes associated with hypertrophy and fibrosis were measured by qRT-PCR. Protein expression (Akt phosphorylation and α-SMA) were assessed by western blotting. Results: ZER significantly suppressed PE-induced increases in cell size, hypertrophic gene expression (ANF and BNP), and Akt phosphorylation in cardiomyocytes. TGF-β-induced increases in collagen synthesis, mRNA levels of POSTN and α-SMA, and protein expression of α-SMA were lower in the ZER-treated cultured cardiac fibroblasts. Echocardiography results showed that left ventricular fractional shortening was increased and wall thickness was reduced in the ZER group compared with the vehicle group. Histological analysis showed that pressure overload-induced cardiac hypertrophy and cardiac fibrosis were inhibited in the ZER group compared with the vehicle group. Conclusions: These results suggest that zerumbone ameliorates pressure overload-induced cardiac dysfunction, at least in part by suppressing both cardiac hypertrophy and fibrosis.