Abstract 11032: Compound A, a Ginger Extract, Significantly Suppresses Pressure Overload-Induced Systolic Dysfunction in Mice

Abstract

Introduction: Cardiac remodeling induced by hypertrophic stresses such as hypertension is a compensatory mechanism associated with cardiomyocyte hypertrophy and cardiac fibrosis. As cardiac remodeling eventually leads to chronic heart failure (HF), there is an urgent need for compounds that can effectively suppress both cardiomyocyte hypertrophy and cardiac fibrosis. In this study, we used a natural compound library to screen for compounds that suppress these two mechanisms with cultured cardiomyocyte and cardiac fibroblasts, and identified compound A, a ginger extract, as a candidate for HF therapy. The purpose of this study is to investigate the effect of compound A on cardiomyocyte hypertrophy and cardiac fibrosis in vitro and on the development of HF in vivo . Methods & Results: First, primary cultured cardiomyocytes were treated with 1 μM of compound A and stimulated with phenylephrine (PE). The results of immunofluorestaining showed that the compound significantly suppressed a PE-induced increase in the surface area of the cells. Quantitative PCR analysis demonstrated that the compound significantly suppressed PE-induced increases in the mRNA levels of hypertrophic response genes such as ANF and BNP. Next, primary cultured cardiac fibroblasts were treated with 1 μM of compound A and then stimulated with transforming growth factor-beta (TGF-β). The results of measurement of L-proline incorporation showed that the compound significantly suppressed TGF-β-induced incorporation. Quantitative PCR and western blotting demonstrated that the compound significantly suppressed TGF-β-induced mRNA and protein levels of α-smooth muscle actin (α-SMA). Finally, C57BL/6J mice were subjected to transverse aortic constriction (TAC) surgery, and were then given a daily oral administration of 1 mg/kg of compound A for 8 weeks. Echocardiographic analysis showed that the compound prevented TAC-induced increases in posterior wall thickness and systolic dysfunction. The compound also suppressed a TAC-induced increase in HW/BW ratio. Conclusions: Compound A suppressed TAC-induced development of HF via the suppression of cardiomyocyte hypertrophy and cardiac fibrosis. These findings suggest that compound A may be an effective agent for HF therapy.