C1q/TNF-related protein 5 contributes to diabetic vascular endothelium dysfunction through promoting Nox-1 signaling
C1q/TNF-related protein 5 contributes to diabetic vascular endothelium dysfunction through promoting Nox-1 signaling
复制标题
C1q/TNF 相关蛋白 5 通过促进 Nox-1 信号传导导致糖尿病血管内皮功能障碍
DOI：
10.1016/j.redox.2020.101476
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发表时间：
2020-07-01
期刊：
影响因子：
11.4
通讯作者：
Wang, Yajing
中科院分区：
文献类型：
--
作者：
Liu, Jing;Meng, Zhijun;Wang, Yajing
目的：脂肪因子表达失调与糖尿病心血管并发症的发生有关。内皮细胞功能障碍是心血管疾病中常见的病理改变，在糖尿病患者中尤为明显.然而，目前尚不清楚是否以及如何失调的脂肪因子可能有助于糖尿病EC功能障碍。方法与结果：在对照/糖尿病患者和对照/糖尿病小鼠（高脂饮食，HFD）中测定血清C1 q/TNF相关蛋白5（CTRP 5）。我们首次观察到糖尿病患者血清总CTRP 5增加，高分子量（HMW）形式减少，但球形（gCTRP 5）显著增加。这些病理改变在糖尿病小鼠中重现。为了确定糖尿病中gCTRP 5增加的病理学意义，进行了体内、离体和体外实验。CTRP 5中和抗体（CTRP 5Ab）的体内给药显著减弱了糖尿病动脉粥样硬化和EC功能障碍。在高糖高脂（HGHL）和糖尿病（HFD）培养的HUVECs中，EC凋亡明显增加。这些病理学改变被gCTRP 5进一步增强，并被CTRP 5Ab减弱。途径特异性发现驱动的方法揭示了Nox 1表达是通常由HFD、HGHL和gCTRP 5激活的信号分子之一。CTRP 5Ab治疗逆转HFD诱导的Nox 1上调。最后，利用Nox 1 siRNA检测Nox 1在gCTRP 5诱导的糖尿病EC凋亡中的作用。结果表明，gCTRP 5激活了糖尿病EC的线粒体凋亡信号，该信号被沉默的Nox 1基因阻断。结论：我们首次证明了gCTRP 5是一种通过Nox 1介导的线粒体凋亡导致糖尿病血管EC功能障碍的新分子，这表明阻断gCTRP 5的干预措施可能保护糖尿病EC功能，最终减轻糖尿病心血管并发症。
Objective: Dysregulated adipokine profiles contribute to the pathogenesis of diabetic cardiovascular complica- tions. Endothelial cell (EC) dysfunction, a common pathological alteration in cardiovascular disorders, is ex- aggerated in diabetes. However, it is unclear whether and how dysregulated adipokines may contribute to diabetic EC dysfunction. Methods and results: Serum C1q/TNF-Related Protein 5 (CTRP5) were determined in control/diabetes patients, and control/diabetic mice (high -fat diet, HFD). We observed for the first time that serum total CTRP5 was increased, high molecular weight (HMW) form was decreased, but the globular form (gCTRP5) was significantly increased in diabetic patients. These pathological alterations were reproduced in diabetic mice. To determine the pathological significance of increased gCTRP5 in diabetes, in vivo, ex vivo and in vitro experiments were per- formed. Diabetic atherosclerosis and EC dysfunction were significantly attenuated by the in vivo administration of CTRP5 neutralization antibody (CTRP5Ab). EC apoptosis was significantly increased in diabetic EC (isolated from HFD animal aorta) or high glucose high lipid (HGHL) cultured HUVECs. These pathological alterations were further potentiated by gCTRP5 and attenuated by CTRP5Ab. Pathway specific discovery -driven approach revealed that Nox1 expression was one of the signaling molecules commonly activated by HFD, HGHL, and gCTRP5. Treatment with CTRP5Ab reversed HFD-induced Nox1 upregulation. Finally, Nox1siRNA was used to determine the causative role of Nox1 in gCTRP5 induced EC apoptosis in diabetes. Results showed that gCTRP5 activated the mitochondrial apoptotic signal of EC in diabetes, which was blocked by the silencing Nox1 gene. Conclusion: We demonstrated for the first time that gCTRP5 is a novel molecule contributing to diabetic vascular EC dysfunction through Nox1-mediated mitochondrial apoptosis, suggesting that interventions blocking gCTRP5 may protect diabetic EC function, ultimately attenuate diabetic cardiovascular complications.