Gallic Acid Suppresses Cardiac Hypertrophic Remodeling and Heart Failure

Abstract

Scope Gallic acid (GA) is a dietary phenolic acid found in tea, red wine, and some plants. It exhibits anti‐oxidative and anti‐inflammatory activities. Recent studies have revealed that GA has beneficial effects against several cardiovascular diseases; however, whether GA attenuates pressure‐overload‐induced cardiac hypertrophy and the underlying mechanism remains unclear. Methods and results Primary cardiomyocyte hypertrophy is stimulated with angiotensin II (Ang II). Cardiac hypertrophic remodeling is induced in mice by transverse aortic constriction (TAC). Myocardial function is evaluated by echocardiographic and hemodynamic analyses, while cardiac tissues are analyzed by histological staining. It is observed that GA significantly decreases Ang II‐induced increases in cardiomyocyte size in vitro. Administration of GA in mice markedly improves TAC‐induced cardiac dysfunction and attenuates pathological changes, including cardiac myocyte hypertrophy, fibrosis, inflammation, and oxidative stress. Mechanistically, GA inhibits ULK1 and activates autophagy, which induces the degradation of EGFR, gp130, and calcineurin A, thereby inhibiting the downstream signaling cascades (AKT, ERK1/2, JAK2/STAT3, and NFATc1). Conclusions The results demonstrate for the first time that GA prevents myocardial hypertrophy and dysfunction via an autophagy‐dependent mechanism. Thus, GA represents a promising therapeutic candidate for treating cardiac hypertrophy and heart failure.

Implication of dietary phenolic acids on inflammation in cardiovascular disease

“…Anti-hypertrophic activity of gallic acid was also seen in the in vitro study of Ang II-induced cardiomyocyte hypertrophy. Mechanistically, gallic acid blocked ULK1 and activated autophagy, which in turn induced EGFR, gp130 and calcineurin A degradation, thereby inhibiting the downstream signalling cascades (JAK2/STAT3, AKT, ERK1/2 and NFATc1) (Yan et al, 2019). Gallic acid also ameliorated sodium arsenite-induced NO elevation and oxidative stress in heart and spleen tissues.…”

Gallic Acid Ameliorates Angiotensin II-Induced Atrial Fibrillation by Inhibiting Immunoproteasome- Mediated PTEN Degradation in Mice

“…Two-dimensional M-mode echocardiography was performed on mice using a 30 MHz probe (Vevo 1100 system; VisualSonics, Toronto, ON, Canada) as described previously ( Wang et al, 2018 ; Chen et al, 2019 ; Yan et al, 2019 ; Zhang et al, 2020 ). The left atrium (LA) chamber dimensions were measured.…”

“…Moreover, GA also reduced cardiac oxidative stress and hypertension by regulating GATA4-NOX signaling in spontaneously hypertensive rats ( Jin et al, 2017 ). Recently, we found that administration of GA attenuated pressure overload-induced cardiac hypertrophic remodeling and heart failure, which are associated with the autophagy-dependent degradation of hypertrophic mediators (EGFR, gp130, and calcineurin A) and the suppression of downstream signaling cascades ( Yan et al, 2019 ). Moreover, GA ameliorated hypertension and vascular remodeling in Ang II-treated mice by suppressing the immunoproteasome-dependent degradation of endothelial nitric oxide synthase ( Yan et al, 2020 ).…”

Deficiency of the Immunoproteasome LMP10 Subunit Attenuates Angiotensin II-Induced Cardiac Hypertrophic Remodeling via Autophagic Degradation of gp130 and IGF1R

“…A recent study suggested that the proteasome inhibitor YSY01A downregulates gp130 and the activation of JAK2 and STAT3 through a lysosome-autophagy pathway in cancer cells (Huang et al, 2017). Moreover, we recently demonstrated that the activation of autophagy by gallic acid induces the degradation of EGFR and gp130, leading to the inhibition of the downstream signaling cascades (Yan et al, 2019). In the present study, we further revealed that LMP10 KO induced autophagy, which promoted the colocalization of IGF1R and gp130 within autophagosomes and their subsequent degradation, leading to the inhibition of downstream mediators (mTOR, AKT STAT3, and ERK1/2) and cardiac hypertrophy (Figures 6, 7), indicating that LMP10 regulates cardiomyocyte hypertrophy via the autophagy-dependent degradation of IGF1R and gp130.…”