C1q/tumor necrosis factor-related protein-3 improves microvascular endothelial function in diabetes through the AMPK/eNOS/NO. signaling pathway
C1q/tumor necrosis factor-related protein-3 improves microvascular endothelial function in diabetes through the AMPK/eNOS/NO. signaling pathway
复制标题
C1q/肿瘤坏死因子相关蛋白-3 通过 AMPK/eNOS/NO· 信号通路改善糖尿病微血管内皮功能
DOI：
10.1016/j.bcp.2021.114745
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发表时间：
2022-01-01
影响因子：
5.8
通讯作者：
Xu, Yong
中科院分区：
文献类型：
--
作者：
Yan, Zheyi;Cao, Xiaoming;Xu, Yong
血管内皮细胞功能障碍的修复是治疗糖尿病相关血管并发症的一种令人鼓舞的方法。研究表明，C1 q/肿瘤坏死因子相关蛋白（CTRP）家族成员可以改善内皮功能。然而，CTRP在糖尿病微血管并发症中的保护特性仍然是未知的。在这里，我们证明了CTRP 3，CTRP 5和CTRP 9的C1q样球状结构域（gCTRP 3，5，9）对微血管产生血管舒张作用，其中gCTRP 3是最强大的一个。在2型糖尿病小鼠模型中，与对照组相比，血清gCTRP 3水平和内皮功能显著降低。两周的gCTRP 3治疗（0.5 μ g/g/d）增强微血管中的内皮依赖性舒张，增加一氧化氮（NO.）减少视网膜血管渗漏。此外，在人视网膜微血管内皮细胞中的蛋白质印迹表明，gCTRP 3触发AMP活化蛋白激酶-α（AMPK α），因此增加内皮NO合酶（eNOS）水平和NO产生。此外，与gCTRP 3在体外孵育改善了由高糖诱导的肠系膜动脉分支中的内皮功能障碍。eNOS或AMPK α的阻断完全消除了上述gCTRP 3的作用。总之，我们首次证明了gCTRP 3通过AMPK/eNOS/NO信号通路改善内皮细胞功能，从而改善糖尿病微血管的血管舒张受损。这一发现可能表明对糖尿病相关微血管并发症的有效干预。
The repair of vascular endothelial cell dysfunction is an encouraging approach for the treatment of vascular complications associated with diabetes. It has been demonstrated that members of C1q/tumor necrosis factor related protein (CTRP) family may improve endothelial function. Nevertheless, the protective properties of CTRPs in diabetic microvascular complications continue to be mostly unknown. Here, we demonstrate that the C1q-like globular domain of CTRP3, CTRP5, and CTRP9 (gCTRP3, 5, 9) exerted a vasorelaxant effect on the microvasculature, of which gCTRP3 was the most powerful one. In a murine model of type 2 diabetes mellitus, serum gCTRP3 level and endothelial function decreased markedly compared with controls. Two weeks of gCTRP3 treatment (0.5 mu g/g/d) enhanced endothelium-dependent relaxation in microvessels, increased nitric oxide (NO.) production, and reduced retinal vascular leakage. In addition, Western blotting in human retinal microvascular endothelial cells indicated that gCTRP3 triggered AMP-activated protein kinase-alpha (AMPK alpha), hence increasing the endothelial NO synthase (eNOS) level and NO. production. In addition, incubation with gCTRP3 in vitro ameliorated the endothelial dysfunction induced by high glucose in the branch of the mesenteric artery. Blockade of either eNOS or AMPK alpha completely abolished the effects of gCTRP3 described above. Taken together, we demonstrate for the first time that gCTRP3 improves impaired vasodilatation of microvasculature in diabetes by ameliorating endothelial cell function through the AMPK/eNOS/NO. signaling pathway. This finding may suggest an effective intervention against diabetes-associated microvascular complications.