Abstract
We investigated the effects and underlying mechanisms of genistein on pathological cardiac hypertrophy in vivo and in vitro. Acardiac hypertrophy model was developed by aortic banding (AB). C57/BL6 mice were randomly assigned to sham+ vehicle (CON), sham+ genistein (GEN), AB+ vehicle (AB), and AB+ genistein groups. Genistein (40 mg/kg/day) was administered by gavage for 7weeks. After assessing the echocardiographic and hemodynamic parameters, mouse hearts were harvested for histopathological and molecular biological analysis. In the in vitro experiments, neonatal rat cardiomyocytes (NRCM) were prepared to test whether genistein could prevent cardiomyocyte hypertrophy induced by phenylephrine (PE). Compared with the CON or GEN group, mice in the AB group exhibited amarkedly increased cross-sectional area of cardiomyocytes, collagen volume fraction, and up-regulated expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), beta-myosin heavy chain (β-MHC) promoter, connective tissue growth factor (CTGF), collagen Iα, collagenIII, fibronectin, transforming growth factor (TGF)-β1, and vimentin mRNA, as well as down-regulated expression of SERCA2α and α‑MHC mRNA. Genistein significantly attenuated the expression of these abnormal hypertrophic and fibrotic markers. This anti-hypertrophic effect might be associated with the inhibition of MAPK (ERK1/2, P38, and JNK1/2) and AKT/GSK-3β signaling. However, in the in vitro experiment, genistein only inhibited hyperphosphorylation of JNK1/2 in the early stage of prohypertrophic stimulation. Genistein could not attenuate PE-induced cardiomyocyte hypertrophy even after pretreatment with sp61005 (aselective inhibitor of JNK1/2). Genistein attenuated pressure overload-induced cardiac hypertrophy in vivo and PE induced NRCM hypertrophy in vitro. The underlying mechanisms of genistein activity may be associated with blocking the JNK1/2 signaling pathways.
Published Version
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