Sleeve Gastrectomy-Induced AMPK Activation Attenuates Diabetic Cardiomyopathy by Maintaining Mitochondrial Homeostasis via NR4A1 Suppression in Rats.
Sleeve Gastrectomy-Induced AMPK Activation Attenuates Diabetic Cardiomyopathy by Maintaining Mitochondrial Homeostasis via NR4A1 Suppression in Rats.
复制标题
袖状胃切除术诱导的 AMPK 激活通过抑制 NR4A1 维持线粒体稳态来减轻大鼠糖尿病心肌病
DOI：
10.3389/fphys.2022.837798
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发表时间：
2022
影响因子：
4
通讯作者：
Zhong M
中科院分区：
文献类型：
--
作者：
Li S;Dong S;Xu Q;Shi B;Li L;Zhang W;Zhu J;Cheng Y;Zhang G;Zhong M
糖尿病性心肌病（DCM）的特征是心肌舒张和收缩功能受损，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），可缓解2型糖尿病（T2 DM），并对心肌功能有益。维持心肌线粒体稳态是DCM的一种有前途的治疗策略。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。采用高脂饲料喂养和小剂量链脲佐菌素注射建立扩张型心肌病大鼠模型。我们观察到SG具有显著的代谢益处，包括体重减轻、食物摄入减少、血糖水平降低以及术后葡萄糖耐量和胰岛素敏感性恢复。SG还能改善心肌肥厚、心肌纤维化、心肌收缩功能障碍和心肌收缩功能障碍，从而延缓DCM的进展。此外，SG通过AMPK信号激活介导的核受体亚家族4 A组成员1（NR 4A 1）/DRP 1抑制恢复线粒体功能障碍和断裂。H9 c2心肌细胞显示AMPK的激活可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SG手术可以减轻DCM中线粒体功能障碍的证据。此外，AMPK激活的NR 4A 1/DRP 1抑制可能是维持心肌线粒体稳态的重要原因，从而有助于DCM的形态和功能缓解。
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 in vivo. 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.
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影响因子：
15.8
作者：
McGlone ER;Carey I;Veličković V;Chana P;Mahawar K;Batterham RL;Hopkins J;Walton P;Kinsman R;Byrne J;Somers S;Kerrigan D;Menon V;Borg C;Ahmed A;Sgromo B;Cheruvu C;Bano G;Leonard C;Thom H;le Roux CW;Reddy M;Welbourn R;Small P;Khan OA
通讯作者：
Khan OA
影响因子：
8.2
作者：
Bugger, Heiko;Abel, E. Dale
通讯作者：
Abel, E. Dale
影响因子：
11.4
作者：
Baixauli, Francesc;Martin-Cofreces, Noa B.;Sanchez-Madrid, Francisco
通讯作者：
Sanchez-Madrid, Francisco
影响因子：
11.8
作者：
Fulco, Marcella;Cen, Yana;Sartorelli, Vittorio
通讯作者：
Sartorelli, Vittorio
影响因子：
29
作者：
Li J;Romestaing C;Han X;Li Y;Hao X;Wu Y;Sun C;Liu X;Jefferson LS;Xiong J;Lanoue KF;Chang Z;Lynch CJ;Wang H;Shi Y
通讯作者：
Shi Y