Chemerin Elicits Potent Constrictor Actions via Chemokine-Like Receptor 1 (CMKLR1), not G-Protein-Coupled Receptor 1 (GPR1), in Human and Rat Vasculature.
Chemerin Elicits Potent Constrictor Actions via Chemokine-Like Receptor 1 (CMKLR1), not G-Protein-Coupled Receptor 1 (GPR1), in Human and Rat Vasculature.
复制标题
DOI：
10.1161/jaha.116.004421
复制
发表时间：
2016-10-14
影响因子：
5.4
通讯作者：
Davenport AP
中科院分区：
文献类型：
--
作者：
Kennedy AJ;Yang P;Read C;Kuc RE;Yang L;Taylor EJ;Taylor CW;Maguire JJ;Davenport AP
趋化素的循环水平在高血压患者中显著升高，且与血压呈正相关。趋化素激活趋化因子样受体1（CMKLR1或ChemR23），并被认为可激活与高血压相关的“孤儿”G蛋白偶联受体1（GPR1）。我们的目的是确定趋化素、CMKLR1和GPR1在人体血管系统中的定位，并确定这些受体中的1个还是2个都介导血管收缩。
通过对动脉导管、静脉和阻力血管进行免疫组织化学和分子生物学研究，我们发现趋化素定位于内皮、平滑肌和外膜，并且CMKLR1和GPR1在平滑肌中广泛表达。C9（趋化素149 - 157）使人隐静脉收缩（pD₂ = 7.30 ± 0.31）和阻力动脉收缩（pD₂ = 7.05 ± 0.54），并使大鼠在200 nmol时血压升高9.1 ± 1.0 mmHg。关键的是，这些体外和体内的血管作用可被CCX832阻断，我们证实CCX832对CMKLR1相对于GPR1具有高度选择性。C9抑制人主动脉平滑肌细胞中的环磷腺苷（cAMP）积累以及预收缩大鼠主动脉，这与观察到的血管收缩作用一致。进一步探索下游信号传导，与趋化素相比，C9对Gi蛋白通路的偏向因子≈5000，表明CMKLR1表现出偏向性激动作用。
我们的数据表明，趋化素作用于CMKLR1而非GPR1来升高血压。趋化素在代谢综合征中具有已确定的有害作用，这些直接的血管作用可能导致高血压，而高血压是心血管疾病的一个额外危险因素。这项研究为选择性CMKLR1拮抗剂的治疗潜力提供了原理验证。
Circulating levels of chemerin are significantly higher in hypertensive patients and positively correlate with blood pressure. Chemerin activates chemokine‐like receptor 1 (CMKLR1 or ChemR23) and is proposed to activate the “orphan” G‐protein‐coupled receptor 1 (GPR1), which has been linked with hypertension. Our aim was to localize chemerin, CMKLR1, and GPR1 in the human vasculature and determine whether 1 or both of these receptors mediate vasoconstriction. Using immunohistochemistry and molecular biology in conduit arteries and veins and resistance vessels, we localized chemerin to endothelium, smooth muscle, and adventitia and found that CMKLR1 and GPR1 were widely expressed in smooth muscle. C9 (chemerin149–157) contracted human saphenous vein (pD 2=7.30±0.31) and resistance arteries (pD 2=7.05±0.54) and increased blood pressure in rats by 9.1±1.0 mm Hg at 200 nmol. Crucially, these in vitro and in vivo vascular actions were blocked by CCX832, which we confirmed to be highly selective for CMKLR1 over GPR1. C9 inhibited cAMP accumulation in human aortic smooth muscle cells and preconstricted rat aorta, consistent with the observed vasoconstrictor action. Downstream signaling was explored further and, compared to chemerin, C9 showed a bias factor=≈5000 for the Gi protein pathway, suggesting that CMKLR1 exhibits biased agonism. Our data suggest that chemerin acts at CMKLR1, but not GPR1, to increase blood pressure. Chemerin has an established detrimental role in metabolic syndrome, and these direct vascular actions may contribute to hypertension, an additional risk factor for cardiovascular disease. This study provides proof of principle for the therapeutic potential of selective CMKLR1 antagonists.