C1q/TNF-related proteins, a family of novel adipokines, induce vascular relaxation through the adiponectin receptor-1/AMPK/eNOS/nitric oxide signaling pathway.
C1q/TNF-related proteins, a family of novel adipokines, induce vascular relaxation through the adiponectin receptor-1/AMPK/eNOS/nitric oxide signaling pathway.
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DOI：
10.1161/atvbaha.111.231050
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Ma XL
中科院分区：
文献类型：
--
作者：
Zheng Q;Yuan Y;Yi W;Lau WB;Wang Y;Wang X;Sun Y;Lopez BL;Christopher TA;Peterson JM;Wong GW;Yu S;Yi D;Ma XL
糖尿病患者血浆脂联素（APN）降低与内皮功能障碍有关。然而，APN敲除动物表现出适度的全身功能障碍，除非代谢受到挑战。蛋白质家族CTRPs （C1q/ tnf相关蛋白）最近被确定为APN的类似物，一些CTRP成员共享APN的代谢调节功能。然而，CTRPs的血管活性仍然是完全未知的。目前已鉴定的小鼠CTRP成员的血管活性在主动脉环中进行了评估，并阐明了huvec中潜在的分子机制。在8个CTRPs中，CTRPs 3、5和9引起明显的血管松弛。CTRP9的血管活性超过APN（3倍），是内皮依赖和一氧化氮（NO）介导的。从机制上讲，CTRP9增加了AMPK/Akt/eNOS磷酸化，增加了NO的产生。AMPK敲除完全阻断ctrp9诱导的Akt/eNOS磷酸化和NO的产生。Akt敲除对ctrp9诱导的AMPK磷酸化无显著影响，但抑制eNOS磷酸化和no生成。脂联素受体1 (AdipoR1)，而非受体2，敲低可阻断ctrp9诱导的AMPK/Akt/eNOS磷酸化和NO的产生。最后，用ampk抑制剂预先孵育血管环可消除ctrp9诱导的血管松弛作用。我们首次提供证据表明CTRP9是一种新型的血管舒张性脂肪细胞因子，可能通过AdipoR1/AMPK/eNOS依赖/NO介导的信号通路发挥血管保护作用。
Reduced plasma adiponectin (APN) in diabetic patients is associated with endothelial dysfunction. However, APN knockout animals manifest modest systemic dysfunction unless metabolically challenged. The protein family CTRPs (C1q/TNF-related proteins) has recently been identified as APN paralogs and some CTRP members share APN’s metabolic regulatory function. However, the vasoactive properties of CTRPs remain completely unknown. The vasoactivity of currently identified murine CTRP members was assessed in aortic vascular rings and underlying molecular mechanisms was elucidated in HUVECs. Of eight CTRPs, CTRPs 3, 5, and 9 caused significant vasorelaxation. The vasoactive potency of CTRP9 exceeded that of APN (3-fold), and is endothelium-dependent and nitric oxide (NO) mediated. Mechanistically, CTRP9 increased AMPK/Akt/eNOS phosphorylation and increased NO production. AMPK knockdown completely blocked CTRP9-induced Akt/eNOS phosphorylation and NO production. Akt knockdown had no significant effect upon CTRP9-induced AMPK phosphorylation, but blocked eNOS phosphorylation and NO production. Adiponectin receptor 1 (AdipoR1), but not receptor 2, knockdown blocked CTRP9-induced AMPK/Akt/eNOS phosphorylation and NO production. Finally, pre-incubating vascular rings with an AMPK-inhibitor abolished CTRP9-induced vasorelaxive effects. We have provided the first evidence that CTRP9 is a novel vasorelaxive adipocytokine which may exert vasculoprotective effects via the AdipoR1/AMPK/eNOS dependent/NO mediated signaling pathway.