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

Abstract

BackgroundCirculating 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.Methods and ResultsUsing 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.ConclusionsOur 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.

Regulatory effect of chemerin and therapeutic efficacy of chemerin‑9 in pancreatogenic diabetes mellitus

“…To evaluate the impact of the cMKlr1 agonist, chemerin-9, on PdM, peritoneal injections of phosphate buffer solution (PBS, 200 µl, control group, n=8) or chemerin-9 (4 µg in 200 µl PBS, n=8) or were performed every day for 42 days, as previously described (17). Blood samples were collected at day 0 and 42.…”

Adipokines and Inflammation: Focus on Cardiovascular Diseases

“…In this line, several studies have shown that chemerin is able to promote contractility in blood vessels, including the pulmonary artery, aorta, and superior mesenteric artery in rats and the human saphenous vein [ 146 , 147 , 148 , 149 , 150 ]. It has also been demonstrated that chemerin promotes the increase of blood pressure in rats and mice [ 149 , 151 , 152 , 153 ].…”

“…In this line, several studies have shown that chemerin is able to promote contractility in blood vessels, including the pulmonary artery, aorta, and superior mesenteric artery in rats and the human saphenous vein [ 146 , 147 , 148 , 149 , 150 ]. It has also been demonstrated that chemerin promotes the increase of blood pressure in rats and mice [ 149 , 151 , 152 , 153 ]. These results are consistent with the presence of increased circulating levels of chemerin in patients with hypertension [ 90 , 125 , 154 , 155 ], where chemerin correlates with inflammatory markers such as TNFα, CRP, and IL-6; metabolic syndrome; and adipose tissue accumulation [ 90 , 125 , 154 ].…”

International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin1) and GPR1 (Chemerin2) Nomenclature, Pharmacology, and Function

“…In addition to activating CMKLR1, human chemerin21 – 157, C9, and C13 have also been found to activate orphan receptor, G protein – coupled receptor 1 (GPR1). This pairing was initially discovered due to the high sequence identity between GPR1 and CMKLR1 ( Barnea et al, 2008 ) and has subsequently been independently confirmed ( Southern et al, 2013 ; Rourke et al, 2014 ; Kennedy et al, 2016 ).…”