Department of Cardiovascular Surgery, Xijing Hospital, 4th Military Medical University, Xian, PR China.
Arterioscler Thromb Vasc Biol. 2011 Nov;31(11):2616-23. doi: 10.1161/ATVBAHA.111.231050.
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 human umbilical vein endothelial cells. Of 8 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 on CTRP9-induced AMPK phosphorylation, but blocked eNOS phosphorylation and NO production. Adiponectin receptor 1, but not receptor 2, knockdown blocked CTRP9-induced AMPK/Akt/eNOS phosphorylation and NO production. Finally, preincubating vascular rings with an AMPK-inhibitor abolished CTRP9-induced vasorelaxative effects.
We have provided the first evidence that CTRP9 is a novel vasorelaxative adipocytokine that may exert vasculoprotective effects via the adiponectin receptor 1/AMPK/eNOS dependent/NO mediated signaling pathway.
糖尿病患者血浆脂联素（APN）减少与内皮功能障碍有关。然而，除非代谢受到挑战，APN 敲除动物表现出轻微的全身功能障碍。C1q/TNF 相关蛋白（CTRPs）蛋白家族最近被鉴定为 APN 旁系同源物，一些 CTRP 成员具有 APN 的代谢调节功能。然而，CTRPs 的血管活性特性仍然完全未知。
在主动脉血管环中评估了目前鉴定出的 8 种 CTRP 成员中的 6 种的血管活性，在人脐静脉内皮细胞中阐明了潜在的分子机制。在 8 种 CTRP 中，CTRP3、CTRP5 和 CTRP9 引起明显的血管舒张。CTRP9 的血管活性效力超过 APN（3 倍），并依赖于内皮和一氧化氮（NO）介导。从机制上讲，CTRP9 增加了 AMPK/Akt/eNOS 磷酸化并增加了 NO 的产生。AMPK 敲低完全阻断了 CTRP9 诱导的 Akt/eNOS 磷酸化和 NO 的产生。Akt 敲低对 CTRP9 诱导的 AMPK 磷酸化没有显著影响，但阻断了 eNOS 磷酸化和 NO 的产生。脂联素受体 1，而不是受体 2，敲低阻断了 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消除了 CTRP9 诱导的血管舒张作用。
我们首次提供了证据表明，CTRP9 是一种新型的血管舒张脂肪因子，可能通过脂联素受体 1/AMPK/eNOS 依赖/NO 介导的信号通路发挥血管保护作用。
