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Rnd3通过促进trim40介导的Rock1泛素化改善糖尿病心脏微血管损伤

Diabetes Pub Date : 2025-04-01 DOI:10.2337/db24-0543

Jie Lin, Xuebin Zhang, Wen Ge, Yu Duan, Xiao Zhang, Yan Zhang, Xinchun Dai, Mengyuan Jiang, Xiaohua Zhang, Jiye Zhang, Huanhuan Qiang, Dongdong Sun

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引用次数: 0

摘要

糖尿病微血管功能障碍表现为内皮细胞连接破坏和微血管通透性增加。然而，针对这些伤害的有效策略仍然很少。本研究采用高脂饮食联合链脲佐菌素注射，在Rnd3内皮特异性转基因和敲除小鼠中建立2型糖尿病小鼠模型。超声心动图评价心功能。采用微血管腐蚀铸型、硝酸镧灌注、经内皮电阻、fitc -葡聚糖渗透性测定和激光散斑造影等方法评价内皮细胞连接处的完整性和微血管功能。利用RNA测序、质谱分析、免疫共沉淀、免疫荧光和分子对接等方法探索Rnd3的下游调控因子。来自功能获得/功能丧失研究的证据表明，Rnd3对糖尿病心脏微血管功能障碍具有保护作用。内皮特异性缺失Rnd3可显著加重糖尿病患者冠状动脉微血管屏障功能障碍，而Rnd3过表达可有效阻止这些影响。此外，Rnd3过表达还可以通过增加LVEF、LVFS和E/A比值来减轻糖尿病小鼠的心功能障碍。Rnd3过表达抑制CMECs凋亡，增加CMECs对HG-PA刺激的迁移。Rnd3过表达抑制HG-PA刺激下cmes中Rock1活性和MLC磷酸化。机械上，Rnd3募集并与E3泛素连接酶Trim40相互作用，进一步促进Rock1的降解，从而抑制hg - pa刺激的cmes内皮屏障的高通透性。然而，在糖尿病患者中，Rnd3的心脏保护作用在很大程度上被Trim40缺乏所取消。综上所述，Rnd3通过调节DCM状态下的Rock1/MLC信号通路，缓解微血管高通透性，维持内皮屏障完整性，减轻心功能障碍。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Rnd3 Ameliorates Diabetic Cardiac Microvascular Injury via Facilitating Trim40-Mediated Rock1 Ubiquitination.

Article highlights: Impaired cardiac microvascular function is a significant contributor to diabetic cardiomyopathy. Rnd3 expression is notably downregulated in cardiac microvascular endothelial cells under diabetic conditions. Rnd3 overexpression mitigates diabetic myocardial microvascular injury and improves cardiac function through the Rock1/myosin light chain signaling pathway. Rnd3 facilitates the recruitment and interaction with Trim40 to promote Rock1 ubiquitination, thereby preserving endothelial barrier integrity in the diabetic heart.

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来源期刊

Diabetes

Diabetes

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