Quercetin Attenuates Cardiac Hypertrophy by Inhibiting Mitochondrial Dysfunction Through SIRT3/PARP-1 Pathway

Abstract

Cardiac hypertrophy is an important characteristic in the development of hypertensive heart disease. Mitochondrial dysfunction plays an important role in the pathology of cardiac hypertrophy. Recent studies have shown that sirtuin 3 (SIRT3)/poly (ADP-ribose) polymerase-1 (PARP-1) pathway modulation inhibits cardiac hypertrophy. Quercetin, a natural flavonol agent, has been reported to attenuate cardiac hypertrophy. However, the molecular mechanism is not completely elucidated. In this study, we aimed to explore the mechanism underlying the protective effect of quercetin on cardiac hypertrophy. Spontaneously hypertensive rats (SHRs) were treated with quercetin (20 mg/kg/d) for 8 weeks to evaluate the effects of quercetin on blood pressure and cardiac hypertrophy. Additionally, the mitochondrial protective effect of quercetin was assessed in H9c2 cells treated with Ang II. SHRs displayed aggravated cardiac hypertrophy and fibrosis, which were attenuated by quercetin treatment. Quercetin also improved cardiac function, reduced mitochondrial superoxide and protected mitochondrial structure in vivo. In vitro, Ang II increased the mRNA level of hypertrophic markers including atrial natriuretic factor (ANF) and β-myosin heavy chain (β-MHC), whereas quercetin ameliorated this hypertrophic response. Moreover, quercetin prevented mitochondrial function against Ang II induction. Importantly, mitochondrial protection and PARP-1 inhibition by quercetin were partly abolished after SIRT3 knockdown. Our results suggested that quercetin protected mitochondrial function by modulating SIRT3/PARP-1 pathway, contributing to the inhibition of cardiac hypertrophy.

Emerging Roles of SIRT3 in Cardiac Metabolism

“…Most recently, Quercetin was identified as SIRT3 activator. It was shown to preserve mitochondrial function and structure, ameliorate cardiac hypertrophy, and improve overall cardiac function via activation of the SIRT3 in spontaneously hypertensive rats (156).…”

Therapeutic Potential of Select Dietary Compounds in the Management of Hypertension and its Cardiovascular Complications

“…Several studies have evaluated the cardioprotective effects of quercetin in an SHR model. Quercetin and its metabolites effectively reduce an increase in blood pressure and heart rate [ 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ] and improve left ventricular [ 62 , 65 , 66 ] and renal hypertrophy [ 62 ]; it enhances the endothelium-dependent aortic vasodilation induced by acetylcholine [ 54 , 57 , 59 , 62 , 63 , 67 , 68 ], but had no effect on the endothelium-independent response induced by nitroprusside [ 54 , 63 , 68 ]. Quercetin also reduces mesenteric contractions in response to phenylephrine, which is associated with depolarization and an increase in smooth muscle intracellular calcium concentration [ 54 , 57 , 58 , 68 , 69 ]; these results suggest that this flavonoid is able to provide vascular protection by ameliorating endothelial dysfunction in a hypertensive model.…”

“…Furthermore, Chen et al reported that quercetin ameliorated the hypertrophic response such as increased mRNA levels of atrial natriuretic factor and β-myosin heavy chain induced by Ang-II in H9C2 cells. The flavonoid was also able to protect against mitochondrial dysfunction by modulation of the sirtuin 3 /poly (ADP-ribose) polymerase-1 pathway, adding to the protective effects against cardiac hypertrophy [ 66 ]. Honcharov et al reported that quercetin treatment leads to significantly improved morphological and functional parameters of the heart by inhibiting trypsin-like and chymotrypsin-like proteasome activities in the aorta and trypsin-like, and peptidyl-glutamyl peptide-hydrolyzing-like activities in the heart [ 71 ].…”

Mechanisms of action of natural small-molecule drugs in cardiovascular disease

“…Persistent hypertrophy leads to cardiac decompensation and systolic dysfunction and exacerbates ventricular remodeling, leading to HF [220]. Multiple natural small molecules treat cardiac hypertrophy through different targets [186][187][188][189][190][191][192][193][194][195][196][197][198][199][200][201][202]; for example, quercetin protects mitochondrial function and inhibits cardiac hypertrophy through SIRT3/PARP-1 signaling [182,184,186,188]. Triptolide increased CDK1 and CDK4 mRNA, CDK1, p21 and p27 mRNA expression [185].…”