C1q/TNF-Related Protein 9 Promotes Revascularization in Response to Ischemia via an eNOS-Dependent Manner
C1q/TNF-Related Protein 9 Promotes Revascularization in Response to Ischemia via an eNOS-Dependent Manner
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DOI：
10.3389/fphar.2020.01313
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发表时间：
2020-08-21
影响因子：
5.6
通讯作者：
Ouchi, Noriyuki
中科院分区：
文献类型：
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作者：
Yamaguchi, Shukuro;Shibata, Rei;Ouchi, Noriyuki
促进血运重建的策略对于缺血性心血管疾病是有价值的。虽然C1 q/TNF相关蛋白（CTRP）9是一种脂联素paranodine与心脏代谢疾病的保护特性，内源性CTRP 9在内皮功能的作用是很大程度上是未知的。本研究旨在探讨CTRP 9在血管重建过程中的作用，并探讨其可能的机制。对CTRP 9敲除（KO）和野生型（WT）小鼠进行单侧后肢缺血手术。与WT小鼠相比，CTRP 9-KO小鼠在缺血肢体中表现出血流恢复受损和毛细血管密度降低。在CTRP 9-KO和WT小鼠中，全身递送表达CTRP 9的腺病毒载体（Ad-CTRP 9）加速血流恢复。用重组CTRP 9蛋白处理增加了培养的人脐静脉内皮细胞（HUVECs）的网络形成和迁移。CTRP 9促进HUVECs中AMP激活激酶（AMPK）、Akt和内皮型一氧化氮合酶（eNOS）的磷酸化。与WT小鼠相比，CTRP 9-KO小鼠还显示缺血肢体中AMPK、Akt和eNOS的磷酸化水平降低。此外，AMPK或Akt信号通路的阻断逆转了CTRP 9刺激的HUVECs中eNOS磷酸化。用NOS抑制剂处理显著减少CTRP 9刺激的HUVEC网络形成和迁移。值得注意的是，Ad-CTRP 9对eNOS-KO小鼠中缺血肢体的血流没有影响。这些结果表明，CTRP 9通过eNOS依赖性机制促进内皮细胞功能和缺血诱导的再血管化，表明CTRP 9代表用于治疗缺血性血管疾病的靶分子。
Strategies to promote revascularization are valuable for ischemic cardiovascular disease. Although C1q/TNF-related protein (CTRP) 9 is an adiponectin paralog with protective properties against cardiometabolic disorders, the role of endogenous CTRP9 in endothelial function is largely unknown. This study aimed to investigate the effects of CTRP9 on revascularization processes and dissected the potential mechanisms. CTRP9-knockout (KO) and wild-type (WT) mice were subjected to unilateral hindlimb ischemic surgery. CTRP9-KO mice exhibited impaired blood flow recovery and decreased capillary density in the ischemic limb compared with WT mice. In both CTRP9-KO and WT mice, systemic delivery of an adenoviral vector expressing CTRP9 (Ad-CTRP9) accelerated blood flow recovery. Treatment with recombinant CTRP9 protein increased network formation and migration of cultured human umbilical vein endothelial cells (HUVECs). CTRP9 promoted the phosphorylation of AMP-activated kinase (AMPK), Akt, and endothelial nitric oxide synthase (eNOS) in HUVECs. CTRP9-KO mice also showed reduced phosphorylation levels of AMPK, Akt, and eNOS in the ischemic limbs compared with WT mice. Furthermore, blockade of AMPK or Akt signaling pathway reversed the CTRP9-stimulated eNOS phosphorylation in HUVECs. Treatment with the NOS inhibitor significantly reduced CTRP9-stimulated network formation and migration of HUVECs. Of note, Ad-CTRP9 had no effects on blood flow of the ischemic limb in eNOS-KO mice. These results indicated that CTRP9 promotes endothelial cell function and ischemia-induced revascularization through the eNOS-dependent mechanism, suggesting that CTRP9 represents a target molecule for treatment of ischemic vascular diseases.