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.
Highlights
Myocardial hypoxia refers to abnormal changes in myocardial function induced in response to an insufficient O2 supply or metabolic disorders and is the primary cause of death [1, 2]
In this study, we examined the protective mechanism of Que against hypoxia/reoxygenation (H/R) stress in human cardiomyocytes and verified whether this antioxidant can improve the vulnerability of cardiomyocytes by regulating mitochondrial and endoplasmic reticulum (ER) functions through silent information regulator protein 1 (SIRT1)/transmembrane BAX inhibitor-1 motif-containing 6 (TMBIM6)
Transfection with SIRT1 short interfering RNA (siRNA) further reduced the viability of human cardiomyocytes and increased apoptosis (Figures 1(c) and 1(d))
Summary
Myocardial hypoxia refers to abnormal changes in myocardial function induced in response to an insufficient O2 supply or metabolic disorders and is the primary cause of death [1, 2]. When cardiomyocytes cannot adapt to the lack of O2 supply, reactive oxygen species (ROS) are overproduced, leading to the development of mitochondrial quality control. Oxidative Medicine and Cellular Longevity disorders and cardiomyocyte apoptosis. Hypoxia can lead to dysfunctions in mitochondrial oxidative phosphorylation [3]. Excessive production of mitochondrial ROS because of mitochondrial respiratory chain dysfunction can affect signal transduction pathways, resulting in lipid peroxidation of the cell membrane and an imbalance in G protein and effector coupling [4]. Mitochondrial dysfunction and disruptions in homeostasis of the intracellular environment are accompanied by endoplasmic reticulum (ER) stress, which further reduces cell viability and accelerates apoptosis [5]. Que exerts pharmacological effects such as regulating mitochondrial quality control and ER function, reducing capillary fragility, lowering blood lipids, and increasing coronary blood flow. Que has been demonstrated to protect cardiomyocytes [7], its underlying mechanism, in the mitochondria and ER, is unclear
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