Quercetin Improves Cardiomyocyte Vulnerability to Hypoxia by Regulating SIRT1/TMBIM6‐Related Mitophagy and Endoplasmic Reticulum Stress

Abstract

Cardiomyocyte apoptosis is an important pathological mechanism underlying cardiovascular diseases and is commonly caused by hypoxia. Moreover, hypoxic injury occurs not only in common cardiovascular diseases but also following various treatments of heart-related conditions. One of the major mechanisms underlying hypoxic injury is oxidative stress. Quercetin has been shown to exert antioxidant stress and vascular protective effects, making it a promising candidate for treating cardiovascular diseases. Therefore, we examined the protective effect of quercetin on human cardiomyocytes subjected to hypoxia-induced oxidative stress damage and its underlying mechanism. Human cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) in vitro with or without quercetin pretreatment; thereafter, flow cytometry, Cell Counting Kit-8 assay, laser scanning confocal microscopy, quantitative PCR, western blotting, and enzyme-linked immunosorbent assay were performed to analyze the effects of quercetin on cardiomyocytes. We found that H/R induced reactive oxygen species overproduction and endoplasmic reticulum stress, as well as inhibited the function of the mitochondria/endoplasmic reticulum and mitophagy, eventually leading to apoptosis and decreasing the viability of human cardiomyocytes. Quercetin pretreatment inhibited H/R-mediated overproduction of reactive oxygen species and damage caused by oxidative stress, increased mitophagy, regulated mRNA and protein expression of transmembrane BAX inhibitor-1 motif-containing 6 (TMBIM6), regulated endoplasmic reticulum stress, and improved the vulnerability of human cardiomyocytes to H/R. Furthermore, transfection with short interfering RNA against silent information regulator protein 1 (SIRT1) counteracted the protective effects of quercetin on cardiomyocytes. Thus, quercetin was predicted to regulate mitophagy and endoplasmic reticulum stress through SIRT1/TMBIM6 and inhibit H/R-induced oxidative stress damage. These findings may be useful for developing treatments for hypoxic injury-induced cardiovascular diseases and further highlight the potential of quercetin for regulating mitochondrial quality control and endoplasmic reticulum function.

Mitophagy Regulation Following Myocardial Infarction

“…Moreover, deletion of PINK1 in this context abrogates the beneficial effect of hydrogen, suggesting that over-activation of PINK1/parkin-mediated mitophagy is essential for the anti-apoptotic and anti-inflammatory effect of hydrogen during cardiac I/R [ 95 ]. Furthermore, several studies showed that pharmacological activation of PINK1/parkin-mediated mitophagy is cardioprotective following H/R [ 103 , 104 , 105 ].…”

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

“…Quercetin is an effective active ingredient extracted from a variety of medicinal plants or Chinese herbal medicines (142,143). It has a good therapeutic effect on cardiovascular diseases.…”

“…In addition, it plays an important role in cardiomyocyte injury. Ji et al (142) studied the pharmacological effects of quercetin on human cardiomyocytes. The study using hypoxia/reoxygenation(H/R)pretreated human cardiomyocytes showed that H/R induced excessive ROS, leading to mitochondrial energy metabolism disorder and endoplasmic reticulum stress, accompanied by a decrease in mitophagy level, finally leading to the apoptosis of cardiomyocytes and a decrease in human cardiomyocyte activity.…”

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

“…Quercetin is a flavonoid that is widely present in nature. Pharmacological studies have reported that quercetin can delay vascular endothelial functional damage and cardiac terminal damage [27]. Quercetin also has a regulatory role in the prevention of myocardial fibrosis [28] and can further regulate islet function.…”

“…Quercetin also has a regulatory role in the prevention of myocardial fibrosis [28] and can further regulate islet function. Moreover, we previously found that quercetin can regulate mitophagy and endoplasmic reticulum stress through SIRT1/TMBIM6, improve mitochondrial energy metabolism, and protect human cardiac myocytes [27]. However, the regulatory mechanisms underlying the effect of quercetin on SIRT5 succinylation and its protective effect on myocardial cells remain unclear.…”