Chemerin Elicits Potent Constrictor Actions via Chemokine-Like Receptor 1 (CMKLR1), not G-Protein-Coupled Receptor 1 (GPR1), in Human and Rat Vasculature

作者: Amanda J. Kennedy , Peiran Yang , Cai Read , Rhoda E. Kuc , Lucy Yang

DOI: 10.1161/JAHA.116.004421

关键词:

摘要: Background 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) is proposed to activate the “orphan” G‐protein‐coupled (GPR1), which has been linked hypertension. Our aim was localize chemerin, CMKLR1, GPR1 human vasculature determine whether both these receptors mediate vasoconstriction. Methods Results Using immunohistochemistry molecular biology conduit arteries veins resistance vessels, we localized endothelium, smooth muscle, adventitia found that CMKLR1 were widely expressed muscle. C9 (chemerin149–157) contracted saphenous vein (pD 2 =7.30±0.31) =7.05±0.54) increased pressure rats by 9.1±1.0 mm Hg at 200 nmol. Crucially, in vitro in vivo vascular actions blocked CCX832, confirmed be highly selective for over GPR1. inhibited cAMP accumulation aortic muscle cells preconstricted rat aorta, consistent observed vasoconstrictor action. Downstream signaling explored further and, compared showed a bias factor=≈5000 G i protein pathway, suggesting exhibits biased agonism. Conclusions data suggest acts but not GPR1, increase an established detrimental role metabolic syndrome, direct may contribute hypertension, additional risk factor cardiovascular disease. This study provides proof principle therapeutic potential antagonists.

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