Wang Yuan, Liu Wentao, Liu Chen, Zhou Zhitong, Chen Sheng, Huang Qianqian, Wang Li, Zeng Guohua, Huang Qiren
Department of Cardiovascular Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People's Republic of China.
Jiangxi Provincial Key Laboratory of Drug Target Discovery and Validation, School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, People's Republic of China.
Am J Physiol Cell Physiol. 2025 Aug 1;329(2):C377-C394. doi: 10.1152/ajpcell.01006.2024. Epub 2025 Jun 25.
Aberrant autophagy mediated by AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/unc-51 like kinase 1 (ULK1) pathway (a canonical autophagy pathway) plays important roles in diabetic cardiomyopathy (DCM). Asprosin (ASP) secreted by white adipose tissue involves in systemic metabolism disorders. However, its role in DCM remains poorly understood. Therefore, the purpose of this study was to investigate its roles and underlying mechanisms in the DCM from the perspective of autophagy and apoptosis. In the in vivo experiments, we observed the effects of ASP deficiency (ASP) or ASP intervention on cardiac function, fibrosis, autophagy, and apoptosis in a diabetes mellitus (DM) mouse model induced by high-fat feeding and streptozotocin (STZ) injection; in the in vitro experiments, we evaluated the effects of ASP intervention with or without 3-methyladenine (3-MA) (autophagy inhibitor) or siAMPK in a H9c2 model injured by high glucose (HG). Our results show that ASP intervention attenuates the myocardial injury induced by DM ( < 0.05) and HG ( < 0.05). In addition, the autophagy level markedly increases ( < 0.05) in diabetic mice, and ASP deficiency worsens the increase induced by DM ( < 0.05). In contrast, ASP intervention alleviates overautophagy induced by DM ( < 0.05) or HG ( < 0.05). Mechanistically, the protective effect of ASP against myocardial injury is through inhibiting the overautophagy mediated by AMPK/mTOR/ULK1 pathway ( < 0.05). Taken together, the findings suggest that ASP would be a potential therapeutic target and the recombinant ASP might be a promising candidate to treat metabolism-associated CVD. Although the findings would present a promise for the treatment of DCM, it is worth noting that the mouse model used fails to fully mimic the human DCM pathophysiology. We demonstrated for the first time that asprosin (ASP) has protective effects against diabetic cardiomyopathy. We found that ASP could stimulate the AMPK/mTOR/ULK1 pathway to reduce the level of autophagy and apoptosis of cardiomyocytes, thereby maintaining the normal physiological function of the heart.
由AMP激活的蛋白激酶（AMPK）/雷帕霉素哺乳动物靶蛋白（mTOR）/unc-51样激酶1（ULK1）途径介导的异常自噬（一种典型的自噬途径）在糖尿病性心肌病（DCM）中起重要作用。白色脂肪组织分泌的脂肪因子（ASP）参与全身代谢紊乱。然而，其在DCM中的作用仍知之甚少。因此，本研究的目的是从自噬和凋亡的角度探讨其在DCM中的作用及潜在机制。在体内实验中，我们观察了脂肪因子缺乏（ASP）或脂肪因子干预对高脂喂养和链脲佐菌素（STZ）注射诱导的糖尿病（DM）小鼠模型心脏功能、纤维化、自噬和凋亡的影响；在体外实验中，我们评估了脂肪因子干预联合或不联合3-甲基腺嘌呤（3-MA，自噬抑制剂）或siAMPK对高糖（HG）损伤的H9c2模型的影响。我们的结果表明，脂肪因子干预可减轻DM（P<0.05）和HG（P<0.（此处原文有误，推测为P<0.05）05）诱导的心肌损伤。此外，糖尿病小鼠的自噬水平显著升高（P<0.05），脂肪因子缺乏会使DM诱导的自噬增加恶化（P<0.05）。相反，脂肪因子干预可减轻DM（P<0.05）或HG（P<0.05）诱导的过度自噬。机制上，脂肪因子对心肌损伤的保护作用是通过抑制AMPK/mTOR/ULK1途径介导的过度自噬（P<0.05）。综上所述，这些发现表明脂肪因子可能是一个潜在的治疗靶点，重组脂肪因子可能是治疗代谢相关心血管疾病的有希望的候选药物。尽管这些发现为DCM的治疗带来了希望，但值得注意的是，所使用的小鼠模型未能完全模拟人类DCM的病理生理学。我们首次证明脂肪因子（ASP）对糖尿病性心肌病具有保护作用。我们发现脂肪因子可以刺激AMPK/mTOR/ULK1途径，降低心肌细胞的自噬和凋亡水平，从而维持心脏的正常生理功能。
