Gentisic acid attenuates pressure overload‐induced cardiac hypertrophy and fibrosis in mice through inhibition of the ERK1/2 pathway

Abstract

We previously reported that gentisic acid (2,5‐dihydroxybenzoic acid) is the third most abundant phenolic component of Dendropanax morbifera branch extracts. Here, we investigated its effects on cardiac hypertrophy and fibrosis in a mouse model of pressure overload and compared them to those of the beta blocker bisoprolol and calcium channel blocker diltiazem. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC). Beginning 2 weeks after this procedure, the mice were given daily intraperitoneal injections of gentisic acid (100 mg/kg/d), bisoprolol (5 mg/kg/d) or diltiazem (10 mg/kg/d) for 3 weeks. Cardiac hypertrophy was evaluated by the heart weight‐to‐body weight ratio, the cardiomyocyte cross‐sectional area after haematoxylin and eosin staining, and echocardiography. Markers of cardiac hypertrophy and fibrosis were tested by reverse transcription‐quantitative real‐time polymerase chain reaction, western blotting and Masson's trichrome staining. The suppressive effects of gentisic acid treatment on TAC‐induced cardiac hypertrophy and fibrosis were comparable to those of bisoprolol administration. Cardiac hypertrophy was reversed and left ventricular septum and posterior wall thickness were restored by gentisic acid, bisoprolol and diltiazem treatment. Cardiac hypertrophic marker gene expression and atrial and brain natriuretic peptide levels were decreased by gentisic acid and bisoprolol, as were cardiac (interstitial and perivascular) fibrosis and fibrosis‐related gene expression. Cardiac hypertrophy‐associated upregulation of the transcription factors GATA4 and Sp1 and activation of extracellular signal‐regulated kinase 1/2 were also negated by these drugs. These results suggest that gentisic acid could serve as a therapeutic agent for cardiac hypertrophy and fibrosis.

A review on gentisic acid as a plant derived phenolic acid and metabolite of aspirin: Comprehensive pharmacology, toxicology, and some pharmaceutical aspects

“…The beneficial effects of GA in a mouse model of cardiac hypertrophy and fibrosis were investigated by Sun et al (). Cardiac hypertrophy and fibrosis were induced in mice by transverse aortic constriction and after 2 weeks mice were given intraperitoneal injections of GA (100 mg·kg·day) for 3 weeks.…”

“…It is demonstrated that GA reversed cardiac hypertrophy and restored left ventricular septum and posterior wall thickness significantly. This article suggested that GA by downregulation of Sp1/GATA4 expression and ERK1/2 signaling pathways demonstrated antihypertrophic and antifibrotic effects (Sun et al, ).…”

Anti-Melanogenic Effect of Dendropanax morbiferus and Its Active Components via Protein Kinase A/Cyclic Adenosine Monophosphate-Responsive Binding Protein- and p38 Mitogen-Activated Protein Kinase-Mediated Microphthalmia−Associated Transcription Factor Downregulation

“…There are some reports that D. morbiferus shows anti-hyperuricemic, antiamnesic, anti-obesity, immunomodulatory, and antiinflammatory activities (Birhanu et al, 2018;Cho et al, 2018;Park et al, 2018a;Park et al, 2018b;Song et al, 2018;Sun et al, 2018b;Choo et al, 2019). The corresponding ingredients isolated from D. morbiferus leaves, such as 1-tetradecanol, dendropanoxide, rutin, gentisic acid, or oleifoliosides, have been reported to have diverse therapeutic potentials (Yu et al, 2012;Lee et al, 2013;Park et al, 2014;Park et al, 2017;Sun et al, 2018a). Recently, D. morbiferus is increasingly interested in functional materials in cosmetics.…”

Role of extracellular signal-regulated kinase 1/2 signaling underlying cardiac hypertrophy

“…Other compounds were also reported to target the ERK pathway. Sun et al [65] showed that Gentisic acid attenuates pressure overload-induced cardiac hypertrophy and fibrosis in mice through inhibition of the ERK1/2 pathway. Additionally, Li et al [66] demonstrated that selumetinib could attenuate pathological and physiological cardiac hypertrophy in vivo caused by pressure overload and swimming.…”