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

View Article: PubMed Central - PubMed

ABSTRACT

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) 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 results: 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 (pD2=7.30±0.31) and resistance arteries (pD2=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.

Conclusions: 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.

No MeSH data available.


Related in: MedlinePlus

Chemerin is a multifaceted protein that is emerging as a potential contributor to cardiovascular disease. This study identifies a novel role of chemerin in modulation of vascular tone in humans. CMKLR1 indicates chemokine‐like receptor 1; SMC, smooth muscle cells.
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jah31763-fig-0009: Chemerin is a multifaceted protein that is emerging as a potential contributor to cardiovascular disease. This study identifies a novel role of chemerin in modulation of vascular tone in humans. CMKLR1 indicates chemokine‐like receptor 1; SMC, smooth muscle cells.

Mentions: Activation of CMKLR1 by chemerin has well‐established roles in inflammation, adipogenesis, and insulin sensitivity, and thus chemerin has a firm role in the pathology of obesity and metabolic syndrome.1 There is increasing recognition of the association between metabolic syndrome and cardiovascular disease. High blood pressure could be a potential link given that it contributes both to metabolic syndrome and is a major risk factor for cardiovascular disease. Circulating chemerin concentration positively correlates with both systolic and diastolic blood pressure in a range of patient populations, particularly those with obesity,48 metabolic syndrome,49, 50, 51, 52 type 2 diabetes mellitus,53, 54 and type 2 diabetes mellitus with hypertension,7 and these patient groups are at higher risk of developing cardiovascular disease. Our data show, for the first time, that chemerin causes concentration‐dependent contraction of human blood vessels and has a direct effect on blood pressure in rats by binding to CMKLR1 on the smooth muscle layer. This allows us to propose a novel mechanism by which chemerin contributes to both cardiovascular disease and metabolic syndrome in addition to its well‐established roles (Figure 9).


Chemerin Elicits Potent Constrictor Actions via Chemokine ‐ Like Receptor 1 ( CMKLR 1), not G ‐ Protein ‐ Coupled Receptor 1 ( GPR 1), in Human and Rat Vasculature
Chemerin is a multifaceted protein that is emerging as a potential contributor to cardiovascular disease. This study identifies a novel role of chemerin in modulation of vascular tone in humans. CMKLR1 indicates chemokine‐like receptor 1; SMC, smooth muscle cells.
© Copyright Policy - creativeCommonsBy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121526&req=5

jah31763-fig-0009: Chemerin is a multifaceted protein that is emerging as a potential contributor to cardiovascular disease. This study identifies a novel role of chemerin in modulation of vascular tone in humans. CMKLR1 indicates chemokine‐like receptor 1; SMC, smooth muscle cells.
Mentions: Activation of CMKLR1 by chemerin has well‐established roles in inflammation, adipogenesis, and insulin sensitivity, and thus chemerin has a firm role in the pathology of obesity and metabolic syndrome.1 There is increasing recognition of the association between metabolic syndrome and cardiovascular disease. High blood pressure could be a potential link given that it contributes both to metabolic syndrome and is a major risk factor for cardiovascular disease. Circulating chemerin concentration positively correlates with both systolic and diastolic blood pressure in a range of patient populations, particularly those with obesity,48 metabolic syndrome,49, 50, 51, 52 type 2 diabetes mellitus,53, 54 and type 2 diabetes mellitus with hypertension,7 and these patient groups are at higher risk of developing cardiovascular disease. Our data show, for the first time, that chemerin causes concentration‐dependent contraction of human blood vessels and has a direct effect on blood pressure in rats by binding to CMKLR1 on the smooth muscle layer. This allows us to propose a novel mechanism by which chemerin contributes to both cardiovascular disease and metabolic syndrome in addition to its well‐established roles (Figure 9).

View Article: PubMed Central - PubMed

ABSTRACT

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) 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 results: 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 (pD2=7.30±0.31) and resistance arteries (pD2=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.

Conclusions: 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.

No MeSH data available.


Related in: MedlinePlus