PDF(Pubmed)
Abstract：
Diabetic cardiomyopathy (DCM) is a major determinant of mortality in diabetic populations, and the potential strategies are insufficient. Canagliflozin has emerged as a potential cardioprotective agent in diabetes, yet its underlying molecular mechanisms remain unclear. We employed a high-glucose challenge (60 mM for 48 h) in vitro to rat cardiomyocytes (H9C2), with or without canagliflozin treatment (20 µM). In vivo, male C57BL/6J mice were subjected to streptozotocin and a high-fat diet to induce diabetes, followed by canagliflozin administration (10, 30 mg·kg-1·d-1) for 12 weeks. Proteomics and echocardiography were used to assess the heart. Histopathological alterations were assessed by the use of Oil Red O and Masson\'s trichrome staining. Additionally, mitochondrial morphology and mitophagy were analyzed through biochemical and imaging techniques. A proteomic analysis highlighted alterations in mitochondrial and autophagy-related proteins after the treatment with canagliflozin. Diabetic conditions impaired mitochondrial respiration and ATP production, alongside decreasing the related expression of the PINK1-Parkin pathway. High-glucose conditions also reduced PGC-1α-TFAM signaling, which is responsible for mitochondrial biogenesis. Canagliflozin significantly alleviated cardiac dysfunction and improved mitochondrial function both in vitro and in vivo. Specifically, canagliflozin suppressed mitochondrial oxidative stress, enhancing ATP levels and sustaining mitochondrial respiratory capacity. It activated PINK1-Parkin-dependent mitophagy and improved mitochondrial function via increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Notably, PINK1 knockdown negated the beneficial effects of canagliflozin on mitochondrial integrity, underscoring the critical role of PINK1 in mediating these protective effects. Canagliflozin fosters PINK1-Parkin mitophagy and mitochondrial function, highlighting its potential as an effective treatment for DCM.
摘要：
糖尿病心肌病（DCM）是糖尿病人群死亡率的主要决定因素，和潜在的战略是不够的。Canagliflozin已成为糖尿病的潜在心脏保护剂，然而其潜在的分子机制仍不清楚。我们在体外对大鼠心肌细胞（H9C2）进行了高葡萄糖攻击（60mM，48小时），有或没有canagliflozin治疗（20µM）。在体内,雄性C57BL/6J小鼠接受链脲佐菌素和高脂肪饮食诱导糖尿病，随后给予canagliflozin（10，30mg·kg-1·d-1）12周。蛋白质组学和超声心动图用于评估心脏。通过使用油红O和Masson三色染色评估组织病理学改变。此外,通过生化和成像技术分析线粒体形态和线粒体自噬。蛋白质组学分析强调了用canagliflozin治疗后线粒体和自噬相关蛋白的变化。糖尿病患者线粒体呼吸和ATP产生受损，同时降低PINK1-Parkin通路的相关表达。高糖条件也降低了PGC-1α-TFAM信号，负责线粒体生物发生。Canagliflozin在体外和体内均可显着减轻心脏功能障碍并改善线粒体功能。具体来说,canagliflozin抑制线粒体氧化应激，提高ATP水平和维持线粒体呼吸能力。它激活了PINK1-Parkin依赖性线粒体自噬，并通过增加磷酸腺苷激活的蛋白激酶（AMPK）的磷酸化来改善线粒体功能。值得注意的是,PINK1敲低否定了canagliflozin对线粒体完整性的有益作用，强调PINK1在介导这些保护作用中的关键作用。Canagliflozin促进PINK1-Parkin线粒体自噬和线粒体功能，强调了其作为DCM有效治疗方法的潜力。
