SIRT5-Related Desuccinylation Modification Contributes to Quercetin-Induced Protection against Heart Failure and High-Glucose-Prompted Cardiomyocytes Injured through Regulation of Mitochondrial Quality Surveillance

Abstract

Myocardial fibrosis represents the primary pathological change associated with diabetic cardiomyopathy and heart failure, and it leads to decreased myocardial compliance with impaired cardiac diastolic and systolic function. Quercetin, an active ingredient in various medicinal plants, exerts therapeutic effects against cardiovascular diseases. Here, we investigate whether SIRT5- and IDH2-related desuccinylation is involved in the underlying mechanism of myocardial fibrosis in heart failure while exploring related therapeutic drugs for mitochondrial quality surveillance. Mouse models of myocardial fibrosis and heart failure, established by transverse aortic constriction (TAC), were administered with quercetin (50 mg/kg) daily for 4 weeks. HL-1 cells were pretreated with quercetin and treated with high glucose (30 mM) in vitro. Cardiac function, western blotting, quantitative PCR, enzyme-linked immunosorbent assay, and immunofluorescence analysis were employed to analyze mitochondrial quality surveillance, oxidative stress, and inflammatory response in myocardial cells, whereas IDH2 succinylation levels were detected using immunoprecipitation. Myocardial fibrosis and heart failure incidence increased after TAC, with abnormal cardiac ejection function. Following high-glucose treatment, HL-1 cell activity was inhibited, causing excess production of reactive oxygen species and inhibition of mitochondrial respiratory complex I/III activity and mitochondrial antioxidant enzyme activity, as well as increased oxidative stress and inflammatory response, imbalanced mitochondrial quality surveillance and homeostasis, and increased apoptosis. Quercetin inhibited myocardial fibrosis and improved cardiac function by increasing mitochondrial energy metabolism and regulating mitochondrial fusion/fission and mitochondrial biosynthesis while inhibiting the inflammatory response and oxidative stress injury. Additionally, TAC inhibited SIRT5 expression at the mitochondrial level and increased IDH2 succinylation. However, quercetin promoted the desuccinylation of IDH2 by increasing SIRT5 expression. Moreover, treatment with si-SIRT5 abolished the protective effect of quercetin on cell viability. Hence, quercetin may promote the desuccinylation of IDH2 through SIRT5, maintain mitochondrial homeostasis, protect mouse cardiomyocytes under inflammatory conditions, and improve myocardial fibrosis, thereby reducing the incidence of heart failure.

Pharmacological Mechanisms of Tinglizi against Chronic Heart Failure Determined by Network Pharmacology and Molecular Docking

“…The mechanism may be to inhibit the activation of MAPK pathway through ROS [ 20 ]. Quercetin inhibited myocardial fibrosis and improved cardiac function by increasing mitochondrial energy metabolism and regulating mitochondrial fusion/fission and mitochondrial biosynthesis while inhibiting the inflammatory response and oxidative stress injury [ 21 ]. Kaempferol (KPF) protects cardiomyocytes from many aspects because of its significant inhibition of inflammatory response and oxidative stress [ 22 ].…”

Role of Mitophagy in Coronary Heart Disease: Targeting the Mitochondrial Dysfunction and Inflammatory Regulation

“…It has a good therapeutic effect on cardiovascular diseases. Wang et al (144) have shown that a certain dose of quercetin can significantly improve myocardial ischemia injury and myocardial fibrosis after acute MI, improve cardiac function and ejection fraction, maintain cardiomyocyte activity, improve mitochondrial energy metabolism in cardiomyocytes, and reduce the incidence of heart failure. Further studies have shown that the therapeutic effect of quercetin may be related to SIRT5 mediated de-succinylation of IDH2 and upregulation of mitophagy (144).…”

“…Wang et al (144) have shown that a certain dose of quercetin can significantly improve myocardial ischemia injury and myocardial fibrosis after acute MI, improve cardiac function and ejection fraction, maintain cardiomyocyte activity, improve mitochondrial energy metabolism in cardiomyocytes, and reduce the incidence of heart failure. Further studies have shown that the therapeutic effect of quercetin may be related to SIRT5 mediated de-succinylation of IDH2 and upregulation of mitophagy (144). However, SIRT5 knockdown eliminated the inhibitory effect of quercetin on the inflammatory response of NLRP3 in cardiomyocytes, and the activity of cardiomyocytes was further reduced.…”

Targeting Cardiovascular Diseases by Flavonols: An Update

“…Chang et al showed that quercetin pretreatment protects human cardiomyocytes from hypoxia-induced oxidative-stress damage by inhibiting reactive-oxygen-species (ROS) production and oxidative-stress damage, improving mitophagy and energy metabolism, regulating mitochondrial/endoplasmic-reticulum function, and reducing apoptosis [ 52 ]. Furthermore, Cheng et al studied the effects of quercetin on mouse models of myocardial fibrosis and heart failure, finding that quercetin administration reduced myocardial fibrosis and enhanced cardiac function in high-glucose-exposed inflammation-injury cardiomyocyte cell line HL-1 [ 53 ]. These effects were partially mediated by increased mitochondrial energy metabolism as well as regulation of mitochondrial fusion/fission and mitochondrial biosynthesis.…”

“…These effects were partially mediated by increased mitochondrial energy metabolism as well as regulation of mitochondrial fusion/fission and mitochondrial biosynthesis. In addition, quercetin reduced the incidence of heart failure by inhibiting the inflammatory response and oxidative-stress injury, protecting mouse cardiomyocytes under inflammatory conditions, and improving myocardial fibrosis [ 53 ]. Similarly, in the ischemia/reperfusion-induced rat model, quercetin exerted cardioprotective effects by inhibiting inflammatory responses and improving contractility potential.…”