Compound a, a ginger extract, significantly prevents pressure overload-induced systolic dysfunction in mice

Introduction: Cardiac remodeling induced by hypertrophic stresses such as hypertension or myocardial infarction is a compensatory mechanism associated with cardiomyocyte hypertrophy and cardiac fibrosis. Since cardiac remodeling eventually leads to systolic dysfunction or decompensated heart failure (HF), there is urgent necessary for compounds that can effectively suppress both cardiomyocyte hypertrophy and cardiac fibrosis. p300, a transcription coactivator with histone acetyltransferase (HAT) activity, plays an important role in the development of HF and maybe a target for HF therapy. In this study, we used a natural compound library to screen for compounds that suppress cardiomyocyte hypertrophy, cardiac fibrosis, and p300-HAT activity with cultured cardiomyocyte, cardiac fibroblasts, and in vitro , 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 cultured cardiomyocyte hypertrophy and cardiac fibrosis and on the development of HF in vivo . Methods & Results: An in vitro p300-HAT assay was performed using compound A. The results revealed that compound A significantly suppressed the acetylation of histone H3K9. Primary cultured cardiomyocytes prepared from neonatal rats were treated with 1 μM of compound A and then stimulated with phenylephrine (PE) for 48 hrs. The results of immunofluorestaining showed that the compound A significantly suppressed PE-induced increase in the surface area of these cells. Quantitative PCR and western blotting analysis demonstrated that compound A significantly suppressed PE-induced increases in the mRNA levels of hypertrophic response genes such as ANF and BNP and histone H3K9 acetylation. 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 A significantly suppressed TGF-β;-induced incorporation. Quantitative PCR and western blotting demonstrated that compound A significantly suppressed TGF-β;-induced mRNA and protein levels of α-smooth muscle actin (α-SMA), and histone H3K9 acetylation. Finally, C57BL/6J mice were subjected to transverse aortic constriction (TAC) surgery and then treated with a daily oral administration of 1 mg/kg of compound A for 8 weeks. Echocardiographic analysis showed that compound A prevented TAC-induced increases in posterior wall thickness and decrease in systolic function. Compound A also suppressed TAC-induced increase in HW/BW ratio and histone H3K9 acetylation. Conclusion: Compound A effectively suppressed pressure overload-induced development of HF by inhibiting p300-HAT activity. This non-toxic dietary compound may be effective for HF therapy in humans.