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) (PMCID:PMC6336978)
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120675.pdf - Accepted Version 3MB |
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: | Harvey, Dr Katie and Alves Moreira Lopes, Dr Rheure and Montezano, Dr Augusto and Nguyen Dinh Cat, Dr Aurelie and Touyz, Professor Rhian and Neves, Dr Karla |
| 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 > School of Cardiovascular & Metabolic Health |
| 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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