Li Songhan, Dong Shuohui, Xu Qian, Shi Bowen, Li Linchuan, Zhang Wenjie, Zhu Jiankang, Cheng Yugang, Zhang Guangyong, Zhong Mingwei
Department of General Surgery, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, China.
Front Physiol. 2022 Mar 10;13:837798. doi: 10.3389/fphys.2022.837798. eCollection 2022.
Diabetic cardiomyopathy (DCM) is characterized by impaired diastolic and systolic myocardial performance and is a major cause of morbidity and mortality in patients with diabetes. Surgical bariatric procedures, such as sleeve gastrectomy (SG), result in remission of type 2 diabetes (T2DM) and have benefits with myocardial function. Maintaining cardiac mitochondrial homeostasis is a promising therapeutic strategy for DCM. However, whether SG surgery affects mitochondrial function and its underlying mechanism remains unclear. This study aimed to investigate the effect of SG surgery on mitochondrial homeostasis and intracellular oxidative stress in rats with DCM. We also examined cellular phenotypes and molecular mechanisms in high glucose and high fat-stimulated myocytes. The rat model of DCM was established by high-fat diet feeding and low-dose streptozotocin injection. We observed a remarkably metabolic benefit of SG, including a reduced body weight, food intake, blood glucose levels, and restored glucose tolerance and insulin sensitivity post-operatively. Also, SG ameliorated the pathological cardiac hypertrophy, myocardial fibrosis and the dysfunction of myocardial contraction and diastole, consequently delayed the progression of DCM. Also, SG restored the mitochondrial dysfunction and fragmentation through the AMPK signaling activation mediated nuclear receptor subfamily 4 group A member 1 (NR4A1)/DRP1 suppression . H9c2 cardiomyocytes showed that activation of AMPK could reverse the mitochondrial dysfunction somehow. Collectively, our study provided evidence that SG surgery could alleviate mitochondrial dysfunction in DCM. Moreover, AMPK-activated NR4A1/DRP1 repression might act as a significant reason for maintaining mitochondrial homeostasis in the myocardium, thus contributing to morphological and functional alleviation of DCM.
糖尿病性心肌病（DCM）的特征是舒张期和收缩期心肌功能受损，是糖尿病患者发病和死亡的主要原因。外科减肥手术，如袖状胃切除术（SG），可导致2型糖尿病（T2DM）缓解，并对心肌功能有益。维持心脏线粒体稳态是治疗DCM的一种有前景的策略。然而，SG手术是否影响线粒体功能及其潜在机制仍不清楚。本研究旨在探讨SG手术对DCM大鼠线粒体稳态和细胞内氧化应激的影响。我们还研究了高糖和高脂刺激的心肌细胞的细胞表型和分子机制。通过高脂饮食喂养和低剂量链脲佐菌素注射建立DCM大鼠模型。我们观察到SG具有显著的代谢益处，包括术后体重减轻、食物摄入量减少、血糖水平降低，以及葡萄糖耐量和胰岛素敏感性恢复。此外，SG改善了病理性心脏肥大、心肌纤维化以及心肌收缩和舒张功能障碍，从而延缓了DCM的进展。此外，SG通过激活AMPK信号介导的核受体亚家族4 A组成员1（NR4A1）/动力相关蛋白1（DRP1）抑制来恢复线粒体功能障碍和碎片化。H9c2心肌细胞表明，AMPK的激活可以在一定程度上逆转线粒体功能障碍。总的来说，我们的研究提供了证据，表明SG手术可以减轻DCM中的线粒体功能障碍。此外，AMPK激活的NR4A1/DRP1抑制可能是维持心肌线粒体稳态的一个重要原因，从而有助于DCM的形态和功能改善。
