Abstract
Cardiac hypertrophy is an adaptive response of the myocardium to pressure overload or adrenergic agonists. Here, we investigated the protective effects and the regulatory mechanism of protocatechuic acid, a phenolic compound, using a mouse model of isoproterenol-induced cardiac hypertrophy. Our results demonstrated that protocatechuic acid treatment significantly downregulated the expression of cardiac hypertrophic markers (Nppa, Nppb, and Myh7), cardiomyocyte size, heart weight to body weight ratio, cross-sectional area, and thickness of left ventricular septum and posterior wall. This treatment also reduced the expression of isoproterenol-induced ROCK1, Sp1, and PKCγ both in vivo and in vitro. To investigate the mechanism, we performed knockdown and overexpression experiments. The knockdown of ROCK1, Sp1, or PKCγ decreased the isoproterenol-induced cell area and the expression of hypertrophic markers, while the overexpression of Sp1 or PKCγ increased the levels of hypertrophic markers. Protocatechuic acid treatment reversed these effects. Interestingly, the overexpression of Sp1 increased cell area and induced PKCγ expression. Furthermore, experiments using transcription inhibitor actinomycin D showed that ROCK1 and Sp1 suppression by protocatechuic acid was not regulated at the transcriptional level. Our results indicate that protocatechuic acid acts via the ROCK1/Sp1/PKCγ axis and therefore has promising therapeutic potential as a treatment for cardiac hypertrophy.
Highlights
Cardiac hypertrophy is an adaptive response of the myocardium to pressure overload or adrenergic agonists
We investigated the effect of protocatechuic acid on cardiac hypertrophy both in vitro and in vivo, as well as the molecular mechanisms involved in these processes
Before we investigated the effect of protocatechuic acid on cardiac hypertrophy, we evaluated protocatechuic acid toxicity in H9c2 cells
Summary
Cardiac hypertrophy is an adaptive response of the myocardium to pressure overload or adrenergic agonists. Our results demonstrated that protocatechuic acid treatment significantly downregulated the expression of cardiac hypertrophic markers (Nppa, Nppb, and Myh7), cardiomyocyte size, heart weight to body weight ratio, cross-sectional area, and thickness of left ventricular septum and posterior wall. This treatment reduced the expression of isoproterenolinduced ROCK1, Sp1, and PKCγ both in vivo and in vitro. It has been reported that GATA4 and GATA6 are involved in the induction of cardiac hypertrophy in vivo and in vitro[21,22] Another transcription factor, located upstream of GATA4, is specificity protein 1 (Sp1); it upregulates the expression of GATA4 and ANP in cardiomyoblast cells[23]. Sp1 is involved in cell growth, differentiation, and c ancer[24,25]
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