第四军医大学付峰研究组取得一项新突破。他们的研究显示，O-GlcNA酰化介导的内皮代谢记忆通过细胞外小泡参与心脏损伤。相关论文于2025年4月2日发表在《细胞—代谢》杂志上。

小组发现，尽管后来胰岛素使血糖正常，长期糖尿病源性血浆小细胞外囊泡（sEV）miR-15-16对健康动物的心肌细胞表现出持续的损害作用，并诱导心功能障碍，表现出记忆特征。动脉内皮细胞是sEV miR-15-16的主要来源。在机制上，sEV miR-15-16的持续释放是由于内皮细胞中CaMK2a/O-GlcNA酰化的高葡萄糖诱导的正反馈循环后CaMK2a的持续激活。在糖尿病患者中，无论血糖或HbA1c如何，sEV miR-15-16升高与心功能障碍显著相关。总之，他们的研究结果表明，糖尿病诱导的O-GlcNA酰化和CaMK2a的激活介导内皮代谢记忆，从而诱导sEV miR-15-16的持续释放和随后的心脏损伤。

研究人员表示，血糖控制良好的糖尿病患者患心力衰竭的风险仍然增加。这一过程可能是由代谢记忆介导的，这一现象表明，即使在血糖正常后，高血糖也会产生长期的负面影响。

附：英文原文

Title: O-GlcNAcylation-mediated endothelial metabolic memory contributes to cardiac damage via small extracellular vesicles

Author: Mingge Ding, Rui Shi, Yanyan Du, Pan Chang, Tian Gao, Dema De, Yunan Chen, Man Li, Jun Li, Ke Li, Shuli Cheng, Xiaoming Gu, Juan Li, Shumiao Zhang, Na Feng, Jianzheng Liu, Min Jia, Rong Fan, Jianming Pei, Chao Gao, Feng Fu

Issue&Volume: 2025-04-02

Abstract: 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.

DOI: 10.1016/j.cmet.2025.03.006

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00109-3