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C1q/TNF-related protein 5 contributes to diabetic vascular endothelium dysfunction through promoting Nox-1 signaling.
Redox Biology ( IF 11.4 ) Pub Date : 2020-02-24 , DOI: 10.1016/j.redox.2020.101476
Jing Liu 1 , Zhijun Meng 1 , Lu Gan 2 , Rui Guo 3 , Jia Gao 3 , Caihong Liu 3 , Di Zhu 2 , Demin Liu 2 , Ling Zhang 2 , Zhen Zhang 2 , Dina Xie 2 , Xiangying Jiao 3 , Wayne Bond Lau 2 , Bernard L Lopez 2 , Theodore A Christopher 2 , Xinliang Ma 2 , Jimin Cao 3 , Yajing Wang 2
Affiliation  

Objective

Dysregulated adipokine profiles contribute to the pathogenesis of diabetic cardiovascular complications. Endothelial cell (EC) dysfunction, a common pathological alteration in cardiovascular disorders, is exaggerated 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 performed. 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.



中文翻译:

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。

客观的

失调的脂肪因子谱有助于糖尿病心血管并发症的发病机制。内皮细胞 (EC) 功能障碍是心血管疾病中常见的病理改变,在糖尿病中被夸大了。然而,尚不清楚失调的脂肪因子是否以及如何导致糖尿病 EC 功能障碍。

方法和结果

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 C1q/TNF 相关蛋白 5 (CTRP5)。我们首次观察到糖尿病患者血清总 CTRP5 升高,高分子量 (HMW) 形式降低,但球状形式 (gCTRP5) 显着升高。这些病理改变在糖尿病小鼠中重现。为了确定增加的 gCTRP5 在糖尿病中的病理意义,进行了体内、离体和体外实验。体内施用 CTRP5 中和抗体 (CTRP5Ab) 可显着减轻糖尿病动脉粥样硬化和 EC 功能障碍。EC 细胞凋亡在糖尿病 EC(从 HFD 动物主动脉分离)或高糖高脂 (HGHL) 培养的 HUVEC 中显着增加。这些病理改变被 gCTRP5 进一步增强,并被 CTRP5Ab 减弱。通路特异性发现驱动的方法表明,Nox1 表达是 HFD、HGHL 和 gCTRP5 通常激活的信号分子之一。CTRP5Ab 治疗可逆转 HFD 诱导的 Nox1 上调。最后,Nox1siRNA 用于确定 Nox1 在 gCTRP5 诱导的糖尿病 EC 凋亡中的致病作用。结果表明,gCTRP5激活了糖尿病EC的线粒体凋亡信号,该信号被沉默的Nox1基因阻断。Nox1siRNA 用于确定 Nox1 在 gCTRP5 诱导的糖尿病 EC 细胞凋亡中的致病作用。结果表明,gCTRP5激活了糖尿病EC的线粒体凋亡信号,该信号被沉默的Nox1基因阻断。Nox1siRNA 用于确定 Nox1 在 gCTRP5 诱导的糖尿病 EC 细胞凋亡中的致病作用。结果表明,gCTRP5激活了糖尿病EC的线粒体凋亡信号,该信号被沉默的Nox1基因阻断。

结论

我们首次证明 gCTRP5 是一种通过 Nox1 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 gCTRP5 的干预措施可以保护糖尿病 EC 功能,最终减轻糖尿病心血管并发症。

更新日期:2020-02-24
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