Cargando…

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

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 lin...

Descripción completa

Detalles Bibliográficos
Autores principales: Kennedy, Amanda J., Yang, Peiran, Read, Cai, Kuc, Rhoda E., Yang, Lucy, Taylor, Emily J. A., Taylor, Colin W., Maguire, Janet J., Davenport, Anthony P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121526/
https://www.ncbi.nlm.nih.gov/pubmed/27742615
http://dx.doi.org/10.1161/JAHA.116.004421
_version_ 1782469425238114304
author Kennedy, Amanda J.
Yang, Peiran
Read, Cai
Kuc, Rhoda E.
Yang, Lucy
Taylor, Emily J. A.
Taylor, Colin W.
Maguire, Janet J.
Davenport, Anthony P.
author_facet Kennedy, Amanda J.
Yang, Peiran
Read, Cai
Kuc, Rhoda E.
Yang, Lucy
Taylor, Emily J. A.
Taylor, Colin W.
Maguire, Janet J.
Davenport, Anthony P.
author_sort Kennedy, Amanda J.
collection PubMed
description 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 (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 G(i) 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.
format Online
Article
Text
id pubmed-5121526
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-51215262016-12-06 Chemerin Elicits Potent Constrictor Actions via Chemokine‐Like Receptor 1 (CMKLR1), not G‐Protein‐Coupled Receptor 1 (GPR1), in Human and Rat Vasculature Kennedy, Amanda J. Yang, Peiran Read, Cai Kuc, Rhoda E. Yang, Lucy Taylor, Emily J. A. Taylor, Colin W. Maguire, Janet J. Davenport, Anthony P. J Am Heart Assoc Original Research 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 (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 G(i) 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. John Wiley and Sons Inc. 2016-10-14 /pmc/articles/PMC5121526/ /pubmed/27742615 http://dx.doi.org/10.1161/JAHA.116.004421 Text en © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Kennedy, Amanda J.
Yang, Peiran
Read, Cai
Kuc, Rhoda E.
Yang, Lucy
Taylor, Emily J. A.
Taylor, Colin W.
Maguire, Janet J.
Davenport, Anthony P.
Chemerin Elicits Potent Constrictor Actions via Chemokine‐Like Receptor 1 (CMKLR1), not G‐Protein‐Coupled Receptor 1 (GPR1), in Human and Rat Vasculature
title Chemerin Elicits Potent Constrictor Actions via Chemokine‐Like Receptor 1 (CMKLR1), not G‐Protein‐Coupled Receptor 1 (GPR1), in Human and Rat Vasculature
title_full Chemerin Elicits Potent Constrictor Actions via Chemokine‐Like Receptor 1 (CMKLR1), not G‐Protein‐Coupled Receptor 1 (GPR1), in Human and Rat Vasculature
title_fullStr Chemerin Elicits Potent Constrictor Actions via Chemokine‐Like Receptor 1 (CMKLR1), not G‐Protein‐Coupled Receptor 1 (GPR1), in Human and Rat Vasculature
title_full_unstemmed Chemerin Elicits Potent Constrictor Actions via Chemokine‐Like Receptor 1 (CMKLR1), not G‐Protein‐Coupled Receptor 1 (GPR1), in Human and Rat Vasculature
title_short Chemerin Elicits Potent Constrictor Actions via Chemokine‐Like Receptor 1 (CMKLR1), not G‐Protein‐Coupled Receptor 1 (GPR1), in Human and Rat Vasculature
title_sort chemerin elicits potent constrictor actions via chemokine‐like receptor 1 (cmklr1), not g‐protein‐coupled receptor 1 (gpr1), in human and rat vasculature
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121526/
https://www.ncbi.nlm.nih.gov/pubmed/27742615
http://dx.doi.org/10.1161/JAHA.116.004421
work_keys_str_mv AT kennedyamandaj chemerinelicitspotentconstrictoractionsviachemokinelikereceptor1cmklr1notgproteincoupledreceptor1gpr1inhumanandratvasculature
AT yangpeiran chemerinelicitspotentconstrictoractionsviachemokinelikereceptor1cmklr1notgproteincoupledreceptor1gpr1inhumanandratvasculature
AT readcai chemerinelicitspotentconstrictoractionsviachemokinelikereceptor1cmklr1notgproteincoupledreceptor1gpr1inhumanandratvasculature
AT kucrhodae chemerinelicitspotentconstrictoractionsviachemokinelikereceptor1cmklr1notgproteincoupledreceptor1gpr1inhumanandratvasculature
AT yanglucy chemerinelicitspotentconstrictoractionsviachemokinelikereceptor1cmklr1notgproteincoupledreceptor1gpr1inhumanandratvasculature
AT tayloremilyja chemerinelicitspotentconstrictoractionsviachemokinelikereceptor1cmklr1notgproteincoupledreceptor1gpr1inhumanandratvasculature
AT taylorcolinw chemerinelicitspotentconstrictoractionsviachemokinelikereceptor1cmklr1notgproteincoupledreceptor1gpr1inhumanandratvasculature
AT maguirejanetj chemerinelicitspotentconstrictoractionsviachemokinelikereceptor1cmklr1notgproteincoupledreceptor1gpr1inhumanandratvasculature
AT davenportanthonyp chemerinelicitspotentconstrictoractionsviachemokinelikereceptor1cmklr1notgproteincoupledreceptor1gpr1inhumanandratvasculature