Ding Mingge, Shi Rui, Du Yanyan, Chang Pan, Gao Tian, De Dema, Chen Yunan, Li Man, Li Jun, Li Ke, Cheng Shuli, Gu Xiaoming, Li Juan, Zhang Shumiao, Feng Na, Liu Jianzheng, Jia Min, Fan Rong, Pei Jianming, Gao Chao, Fu Feng
Department of Geriatrics Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi, China; Key Laboratory of Surgical Critical Care and Life Support, Xi'an Jiaotong University, Ministry of Education, Xi'an 710004, Shaanxi, China.
Department of Geriatrics Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi, China; Key Laboratory of Surgical Critical Care and Life Support, Xi'an Jiaotong University, Ministry of Education, Xi'an 710004, Shaanxi, China; Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, Shaanxi, China.
Cell Metab. 2025 Jun 3;37(6):1344-1363.e6. doi: 10.1016/j.cmet.2025.03.006. Epub 2025 Apr 2.
Diabetic individuals with well-controlled blood glucose still have an increased risk of heart failure. This process may be mediated by metabolic memory, a phenomenon showing that hyperglycemia has long-term negative effects even after normoglycemia. Here, we found that despite later normoglycemia with insulin, long-term diabetes-derived plasma small extracellular vesicle (sEV) miR-15-16 exhibited sustained deleterious effects on cardiomyocytes and induced cardiac dysfunction in healthy animals, displaying a memory feature. Artery endothelial cells were the primary origin of sEV miR-15-16. Mechanistically, the continuous sEV miR-15-16 release is due to the sustained activation of CaMK2a following the high glucose-elicited positive feedback loop of CaMK2a/O-GlcNAcylation in endothelial cells. In patients with diabetes, elevated sEV miR-15-16 was significantly associated with cardiac dysfunction, regardless of blood glucose or HbA1c. Together, our findings demonstrate that diabetes-induced O-GlcNAcylation and activation of CaMK2a mediate endothelial metabolic memory, which induces continuous release of sEV miR-15-16 and subsequent cardiac damage.
血糖控制良好的糖尿病患者发生心力衰竭的风险仍然增加。这一过程可能由代谢记忆介导，代谢记忆是一种现象，表明即使在血糖正常后，高血糖仍具有长期负面影响。在这里，我们发现，尽管后来使用胰岛素使血糖正常，但长期糖尿病来源的血浆小细胞外囊泡（sEV）miR-15-16对心肌细胞仍有持续的有害影响，并在健康动物中诱发心脏功能障碍，表现出记忆特征。动脉内皮细胞是sEV miR-15-16的主要来源。从机制上讲，sEV miR-15-16的持续释放是由于内皮细胞中CaMK2a/O-GlcNAcylation的高糖诱导正反馈环导致CaMK2a持续激活。在糖尿病患者中，无论血糖或糖化血红蛋白水平如何，sEV miR-15-16升高均与心脏功能障碍显著相关。总之，我们的研究结果表明，糖尿病诱导的O-GlcNAcylation和CaMK2a激活介导了内皮代谢记忆，从而诱导sEV miR-15-16的持续释放和随后的心脏损伤。
