Zhang Lin, Zhang Heming, Xie Xiuzhu, Tie Ruping, Shang Xiaolin, Zhao Qianqian, Xu Junjie, Jin Liyuan, Zhang Jinying, Ye Ping
Medical School of Chinese PLA, Department of Geriatric Cardiology, The Second Medical Centre, Chinese PLA General Hospital, Beijing, China.
Department of Anesthesiology, The 963 Hospital of the PLA Joint Logistics Support Force, Jiamusi, China.
Diabetol Metab Syndr. 2023 May 6;15(1):93. doi: 10.1186/s13098-023-01061-6.
Empagliflozin, a sodium-glucose co-transporter 2 inhibitor (SGLT2i), has been reported to significantly reduce the risk of heart failure in multiple clinical studies. However, the underlying mechanisms remain elusive. This study aimed to investigate the effect of empagliflozin on branched-chain amino acid (BCAA) metabolism in diabetic cardiomyopathy.
Thirty male 8-week KK Cg-Ay/J mice were used to study diabetic cardiomyopathy; here, 15 were used as the model group, and the remaining 15 were administered empagliflozin (3.75 mg/kg/day) by gavage daily for 16 weeks. The control group consisted of fifteen male 8-week C57BL/6J mice, whose blood glucose and body weight were measured simultaneously with the diabetic mice until 16 weeks without additional intervention. Echocardiography and histopathology were performed to evaluate cardiac structure and function. Proteomic sequencing and biogenic analysis were performed on mouse hearts. Parallel Reaction Monitoring and western blotting were performed to validate the expression levels of differentially expressed proteins.
The results showed that empagliflozin improved ventricular dilatation and ejection fraction reduction in diabetic hearts, as well as the elevation of myocardial injury biomarkers hs-cTnT and NT-proBNP. At the same time, empagliflozin alleviates myocardial inflammatory infiltration, calcification foci deposition, and fibrosis caused by diabetes. The results of the proteomics assay showed that empagliflozin could improve the metabolism of various substances, especially promoting the BCAA metabolism of diabetic hearts by up-regulating PP2Cm. Furthermore, empagliflozin could affect the mTOR/p-ULK1 signaling pathway by reducing the concentration of BCAA in diabetic hearts. When mTOR/p-ULK1 protein was inhibited, ULK1, the autophagy initiation molecule, increased. Moreover, autophagy substrate p62 and autophagy marker LC3B were significantly reduced, indicating that the autophagy activity of diabetes inhibition was reactivated.
Empagliflozin may attenuate diabetic cardiomyopathy-related myocardial injury by promoting the catabolism of BCAA and inhibiting mTOR/p-ULK1 to enhance autophagy. These findings suggest that empagliflozin could be a potential candidate drug against BCAA increase and could be used for other cardiovascular diseases with a metabolic disorder of BCAA.
恩格列净是一种钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i），多项临床研究报告称其可显著降低心力衰竭风险。然而，其潜在机制仍不清楚。本研究旨在探讨恩格列净对糖尿病性心肌病中支链氨基酸（BCAA）代谢的影响。
选用30只8周龄雄性KK Cg-Ay/J小鼠研究糖尿病性心肌病；其中15只作为模型组，其余15只每天经口灌胃给予恩格列净（3.75mg/kg/天），持续16周。对照组由15只8周龄雄性C57BL/6J小鼠组成，在16周内与糖尿病小鼠同时测量血糖和体重，不进行额外干预。进行超声心动图和组织病理学检查以评估心脏结构和功能。对小鼠心脏进行蛋白质组测序和生物信息学分析。采用平行反应监测和蛋白质印迹法验证差异表达蛋白的表达水平。
结果显示，恩格列净改善了糖尿病心脏的心室扩张和射血分数降低，以及心肌损伤生物标志物hs-cTnT和NT-proBNP的升高。同时，恩格列净减轻了糖尿病引起的心肌炎性浸润、钙化灶沉积和纤维化。蛋白质组学分析结果表明，恩格列净可改善各种物质的代谢，尤其是通过上调PP2Cm促进糖尿病心脏的BCAA代谢。此外，恩格列净可通过降低糖尿病心脏中BCAA的浓度来影响mTOR/p-ULK1信号通路。当mTOR/p-ULK1蛋白被抑制时，自噬起始分子ULK1增加。此外，自噬底物p62和自噬标志物LC3B显著降低，表明糖尿病抑制的自噬活性被重新激活。
恩格列净可能通过促进BCAA的分解代谢和抑制mTOR/p-ULK1以增强自噬来减轻糖尿病性心肌病相关的心肌损伤。这些发现表明，恩格列净可能是一种针对BCAA升高的潜在候选药物，可用于其他伴有BCAA代谢紊乱的心血管疾病。
