Abstract
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.
Highlights
Diabetic cardiomyopathy (DCM) is defined as a distinct disease entity that occurs in patients with diabetes mellitus (DM) independent of coronary artery disease, hypertension, or valvular heart disease (Jia et al, 2018; Tan et al, 2020)
General Characteristics and Glucose Homeostasis in Rats With Obesity and Type 2 Diabetes Mellitus Was Significantly Ameliorated After Sleeve Gastrectomy
Rats in the sham group were only hypophagic during the first week, while the appetitive deficit of rats in the sleeve gastrectomy (SG) group lasted for a long time, which enabled the maintenance of a reduced body weight (Figure 1B)
Summary
Diabetic cardiomyopathy (DCM) is defined as a distinct disease entity that occurs in patients with diabetes mellitus (DM) independent of coronary artery disease, hypertension, or valvular heart disease (Jia et al, 2018; Tan et al, 2020). During the early phases of diabetes, an absence of insulin or insulin resistance initiates a metabolic alteration in cardiomyocytes, which leads to the activation of fatty acid uptake and β-oxidation to ensure adequate adenosine-triphosphate (ATP) generation. Increased fatty acid concentrations subsequently result in mitochondrial dysfunction and an elevated accumulation of reactive oxygen species (ROS) (Tan et al, 2020). These pathological transformations result in cardiomyocyte death, inflammation, and fibrotic remodeling (Jia et al, 2018). Adenosine monophosphate-activated protein kinase (AMPK) plays an important role in metabolic diseases (Hoffman et al, 2015). Under DCM conditions, the activation of energy deprivation sensors, sirtuin-1 (SIRT1) and phosphorylation of AMPK can promote the removal of dysfunctional mitochondria and peroxisomes to reverse the development of cardiomyopathy (Packer, 2020a). AMPK signaling shows promising potential as a novel target for DCM treatment
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