Protocatechuic acid attenuates isoproterenol-induced cardiac hypertrophy via downregulation of ROCK1–Sp1–PKCγ axis

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.

Syringic acid mitigates isoproterenol‐induced cardiac hypertrophy and fibrosis by downregulating Ereg

“…20 The transcription factors GATA4, GATA6 and SP1 are reported to induce cardiac hypertrophy. 14,21 However, EREG does not directly increase cardiomyocyte size. The findings of this study suggest that EREG partially contributes to cardiac hypertrophy.…”

“…Additionally, EREG promoted the migration of salivary adenoid cystic carcinoma cells by upregulating the phosphorylation of ERK, Akt, STAT3 and EGFR 20 . The transcription factors GATA4, GATA6 and SP1 are reported to induce cardiac hypertrophy 14,21 . However, EREG does not directly increase cardiomyocyte size.…”

“…Gallic acid, gentisic acid, protocatechuic acid, syringic acid and vanillic acid belong to the class of benzoic acids 11 . Recently, we had reported that gallic acid, gentisic acid or protocatechuic acid alleviated cardiac hypertrophy and fibrosis in the isoproterenol or pressure overload‐induced hypertrophy mouse models 12–14 . Several phytochemicals, including apigenin, baicalein, berberine hydrochloride and emodin, suppress stress‐induced hypertrophy 15 .…”

“…11 Recently, we had reported that gallic acid, gentisic acid or protocatechuic acid alleviated cardiac hypertrophy and fibrosis in the isoproterenol or pressure overload-induced hypertrophy mouse models. [12][13][14] Several phytochemicals, including apigenin, baicalein, berberine hydrochloride and emodin, suppress stress-induced hypertrophy. 15 However, the therapeutic effects of syringic acid on cardiac hypertrophy have not been elucidated.…”

PRKCE non-coding variants influence on transcription as well as translation of its gene

“…Hence, mutated PKCε gene regulated its own transcription. Studies also indicated that Ap1 regulates the expression of PKC iota in cardiac hypertrophy [ 81 ]. This might be the principal mechanism behind the PKCε pathogenicity in different diseases specifically cancers, where its over expression is frequently reported.…”