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.

中文翻译：

---

SIRT5 相关的去琥珀酰化修饰有助于槲皮素通过调节线粒体质量监测来预防心力衰竭和高糖诱导的心肌细胞损伤

心肌纤维化是与糖尿病性心肌病和心力衰竭相关的主要病理变化，它导致心肌顺应性降低，心脏舒张和收缩功能受损。槲皮素是多种药用植物中的活性成分，对心血管疾病具有治疗作用。在这里，我们研究了 SIRT5 和 IDH2 相关的脱琥珀酰化是否参与心力衰竭心肌纤维化的潜在机制，同时探索线粒体质量监测的相关治疗药物。通过横向主动脉缩窄 (TAC) 建立的心肌纤维化和心力衰竭小鼠模型每天服用槲皮素 (50 mg/kg)，持续 4 周。HL-1 细胞用槲皮素预处理并用高葡萄糖 (30 mM) 处理体外. 采用心功能、蛋白质印迹、定量 PCR、酶联免疫吸附试验和免疫荧光分析来分析心肌细胞的线粒体质量监测、氧化应激和炎症反应，而使用免疫沉淀法检测 IDH2 琥珀酰化水平。TAC后心肌纤维化和心力衰竭发生率增加，心脏射血功能异常。高糖处理后，HL-1细胞活性受到抑制，导致活性氧产生过多，线粒体呼吸复合物I/III活性和线粒体抗氧化酶活性受到抑制，氧化应激和炎症反应增加，线粒体质量不平衡监测和体内平衡，并增加细胞凋亡。槲皮素通过增加线粒体能量代谢，调节线粒体融合/裂变和线粒体生物合成，同时抑制炎症反应和氧化应激损伤，抑制心肌纤维化，改善心脏功能。此外，TAC 在线粒体水平抑制 SIRT5 表达并增加 IDH2 琥珀酰化。然而，槲皮素通过增加 SIRT5 的表达来促进 IDH2 的脱琥珀酰化。此外，用 si-SIRT5 处理消除了槲皮素对细胞活力的保护作用。因此，槲皮素可能通过SIRT5促进IDH2去琥珀酰化，维持线粒体稳态，保护炎症条件下的小鼠心肌细胞，改善心肌纤维化，从而降低心力衰竭的发生率。