Chemerin receptor blockade improves vascular function in diabetic obese mice via redox-sensitive- and Akt-dependent pathways

Neves, K. B. , Nguyen Dinh Cat, A., Alves-Lopes, R. , Harvey, K. Y., da Costa, R. M., Lobato, N. S., Montezano, A. C., Oliveira, A. M., Touyz, R. M. and Tostes, R. C. (2018) Chemerin receptor blockade improves vascular function in diabetic obese mice via redox-sensitive- and Akt-dependent pathways. American Journal of Physiology: Heart and Circulatory Physiology, 315(6), H1851-H1860. (doi:10.1152/ajpheart.00285.2018) (PMID:30216119)

Neves, K. B. , Nguyen Dinh Cat, A., Alves-Lopes, R. , Harvey, K. Y., da Costa, R. M., Lobato, N. S., Montezano, A. C., Oliveira, A. M., Touyz, R. M. and Tostes, R. C. (2018) Chemerin receptor blockade improves vascular function in diabetic obese mice via redox-sensitive- and Akt-dependent pathways. American Journal of Physiology: Heart and Circulatory Physiology, 315(6), H1851-H1860. (doi:10.1152/ajpheart.00285.2018) (PMID:30216119)

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Abstract

Chemerin and its G protein-coupled receptor [chemerin receptor 23 (ChemR23)] have been associated with endothelial dysfunction, inflammation, and insulin resistance. However, the role of chemerin on insulin signaling in the vasculature is still unknown. We aimed to determine whether chemerin reduces vascular insulin signaling and whether there is interplay between chemerin/ChemR23, insulin resistance, and vascular complications associated with type 2 diabetes (T2D). Molecular and vascular mechanisms were probed in mesenteric arteries and cultured vascular smooth muscle cells (VSMCs) from C57BL/6J, nondiabetic lean db/m, and diabetic obese db/db mice as well as in human microvascular endothelial cells (HMECs). Chemerin decreased insulin-induced vasodilatation in C57BL/6J mice, an effect prevented by CCX832 (ChemR23 antagonist) treatment. In VSMCs, chemerin, via oxidative stress- and ChemR23-dependent mechanisms, decreased insulin-induced Akt phosphorylation, glucose transporter 4 translocation to the membrane, and glucose uptake. In HMECs, chemerin decreased insulin-activated nitric oxide signaling. AMP-activated protein kinase phosphorylation was reduced by chemerin in both HMECs and VSMCs. CCX832 treatment of db/db mice decreased body weight, insulin, and glucose levels as well as vascular oxidative stress. CCX832 also partially restored vascular insulin responses in db/db and high-fat diet-fed mice. Our novel in vivo findings highlight chemerin/ChemR23 as a promising therapeutic target to limit insulin resistance and vascular complications associated with obesity-related diabetes.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Montezano, Dr Augusto and Harvey, Dr Katie and Nguyen Dinh Cat, Dr Aurelie and Lopes, Dr Rheure and Touyz, Professor Rhian and Neves, Dr Karla Bianca
Authors: Neves, K. B., Nguyen Dinh Cat, A., Alves-Lopes, R., Harvey, K. Y., da Costa, R. M., Lobato, N. S., Montezano, A. C., Oliveira, A. M., Touyz, R. M., and Tostes, R. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:American Journal of Physiology: Heart and Circulatory Physiology
Publisher:American Physiological Society
ISSN:0363-6135
ISSN (Online):1522-1539
Published Online:14 September 2018
Copyright Holders:Copyright © 2018 American Physiological Society
First Published:First published in American Journal of Physiology: Heart and Circulatory Physiology 315(6): H1851-H1860
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
617771BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177RI CARDIOVASCULAR & MEDICAL SCIENCES
607381Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)CH/12/4/29762RI CARDIOVASCULAR & MEDICAL SCIENCES