Alpha Mangostin Derived from Garcinia magostana Linn Ameliorates Cardiomyocyte Hypertrophy and Fibroblast Phenotypes in Vitro

Cardiac hypertrophy and fibrosis are significant risk factors for chronic heart failure (HF). Since pharmacotherapy agents targeting these processes have not been established, we investigated the effect of alphamagostin (alpha-man) on cardiomyocyte hypertrophy and fibrosis in vitro. Primary cultured cardiomyocytes and cardiac fibroblasts were prepared from neonatal rats. After alpha-man treatment, phenylephrine (PE) and transforming growth factor-beta (TGF-beta) were added to the cardiomyocytes and cardiac fibroblasts to induce hypertrophic and fibrotic responses, respectively. Hypertrophic responses were assessed by measuring the cardiomyocyte surface area and hypertrophic gene expression levels. PE-induced phosphorylation of Akt, extracellular signal-regulated kinase (ERK)1/2, and p38 was examined by Western blotting. Fibrotic responses were assessed by measuring collagen synthesis, fibrotic gene expression levels, and myofibroblast differentiation. In addition, TGF-beta-induced reactive oxygen species (ROS) production was investigated. In cultured cardiomyocytes, alpha-man significantly suppressed PE-induced increases in the cardiomyocyte surface area, and the mRNA levels (atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP)). Treatment with alpha-man significantly suppressed PE-induced Akt phosphorylation, but not ERK and p38 phosphorylation. In cultured cardiac fibroblasts, alpha-man significantly suppressed TGF-beta-induced increases in L-proline incorporation, mRNA levels (POSTN and alpha-smooth muscle actin (alpha-SMA)), and myofibroblast differentiation. Additionally, it significantly inhibited TGF-beta-induced reduced nicotinamide adenine dinucleotide phosphate oxidase4 (NOX4) expression and ROS production in cardiac fibroblasts. Treatment with alpha-man significantly ameliorates hypertrophy by inhibiting Akt phosphorylation in cardiomyocytes and fibrosis by inhibiting NOX4-generating ROS in fibroblasts. These findings suggest that alpha-man is a possible natural product for the prevention of cardiac hypertrophy and fibrosis.