恩格列净通过激活 SIRT3 介导的自噬体形成缓解肥胖相关的心脏功能障碍。
Empagliflozin alleviates obesity-related cardiac dysfunction via the activation of SIRT3-mediated autophagosome formation.
机构信息
Department of Endocrinology and Metabolism, Clinical Research Center, Shandong Provincial Key Medical and Health Discipline of Endocrinology, Affiliated Hospital of Shandong Second Medical University, Weifang, 261031, China.
Department of Pathology, Affiliated Hospital of Shandong Second Medical University, Weifang, 261031, China.
出版信息
Lipids Health Dis. 2024 Sep 27;23(1):308. doi: 10.1186/s12944-024-02293-9.
BACKGROUND
Empagliflozin (EMPA) has demonstrated efficacy in providing cardiovascular benefits in metabolic diseases. However, the direct effect of EMPA on autophagy in obesity-related cardiac dysfunction remains unclear. Therefore, this study aimed to determine changes in cardiac autophagy during diet-induced obesity and clarify the exact mechanism by which EMPA regulates autophagic pathways.
METHODS
Male C57BL/6J mice were fed a 12-week high-fat diet (HFD) followed by 8 weeks of EMPA treatment. Body composition analysis and echocardiography were performed to evaluate metabolic alterations and cardiac function. Histological and immunofluorescence staining was used to evaluate potential enhancements in myocardial structure and biological function. Additionally, H9c2 cells were transfected with small interfering RNA targeting sirtuin 3 (SIRT3) and further treated with palmitic acid (PA) with or without EMPA. Autophagy-related targets were analyzed by western blotting and RT‒qPCR.
RESULTS
EMPA administration effectively ameliorated metabolic disorders and cardiac diastolic dysfunction in HFD-fed mice. EMPA prevented obesity-induced myocardial hypertrophy, fibrosis, and inflammation through the activation of SIRT3-mediated autophagosome formation. The upregulation of SIRT3 triggered by EMPA promoted the initiation of autophagy by activating AMP-activated protein kinase (AMPK) and Beclin1. Furthermore, activated SIRT3 contributed to the elongation of autophagosomes through autophagy-related 4B cysteine peptidase (ATG4B) and autophagy-related 5 (ATG5).
CONCLUSIONS
EMPA promotes SIRT3-mediated autophagosome formation to alleviate damage to the cardiac structure and function of obese mice. Activated SIRT3 initiates autophagy through AMPK/Beclin1 and further stimulates elongation of the autophagosome membrane via ATG4B/ATG5. These results provide a new explanation for the cardioprotective benefits of EMPA in obesity.
背景
恩格列净（EMPA）已被证明在代谢疾病中具有提供心血管益处的功效。然而，EMPA 对肥胖相关心功能障碍中自噬的直接影响尚不清楚。因此，本研究旨在确定饮食诱导肥胖过程中心脏自噬的变化，并阐明 EMPA 调节自噬途径的确切机制。
方法
雄性 C57BL/6J 小鼠喂食 12 周高脂肪饮食（HFD），然后接受 8 周 EMPA 治疗。进行身体成分分析和超声心动图检查，以评估代谢变化和心脏功能。组织学和免疫荧光染色用于评估心肌结构和生物学功能的潜在增强。此外，用小干扰 RNA 靶向沉默 3（SIRT3）转染 H9c2 细胞，并进一步用棕榈酸（PA）与 EMPA 共处理。通过 Western blot 和 RT-qPCR 分析自噬相关靶标。
结果
EMPA 给药可有效改善 HFD 喂养小鼠的代谢紊乱和舒张性心功能障碍。EMPA 通过激活 SIRT3 介导的自噬体形成，预防肥胖引起的心肌肥大、纤维化和炎症。EMPA 上调 SIRT3 通过激活 AMP 激活的蛋白激酶（AMPK）和 Beclin1 来启动自噬。此外，激活的 SIRT3 通过自噬相关 4B 半胱氨酸肽酶（ATG4B）和自噬相关 5（ATG5）促进自噬体的延伸。
结论
EMPA 促进 SIRT3 介导的自噬体形成，以减轻肥胖小鼠心脏结构和功能的损伤。激活的 SIRT3 通过 AMPK/Beclin1 启动自噬，进一步通过 ATG4B/ATG5 刺激自噬体膜的延伸。这些结果为 EMPA 在肥胖中的心脏保护益处提供了新的解释。
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