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

Author(s)

Neves, Karla Bianca ^{[1, 2]} ; Cat, Aurelie Nguyen Dinh ^[1] ; Alves-Lopes, Rheure ^{[3, 1]} ; Harvey, Katie Yates ^[1] ; da Costa, Rafael Menezes ^[3] ; Lobato, Nubia Souza ^[4] ; Montezano, Augusto Cesar ^[1] ; de Oliveira, Ana Maria ^[2] ; Touyz, Rhian M. ^[1] ; Tostes, Rita C. ^[3]

Affiliation

^[1] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark - Scotland

^[2] Univ Sao Paulo, Fac Pharmaceut Sci Ribeirao Preto, Dept Phys & Chem, Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Sao Paulo - Brazil

^[4] Univ Fed Goias, Dept Biol Sci, Jatai, Go - Brazil

• Document type: Journal article
• Source: AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY; v. 315, n. 6, p. H1851-H1860, DEC 2018.
• Web of Science Citations: 6

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 LIMECs 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. NEW \& NOTEWORTHY Our novel findings show that the chemerin/chemerin receptor 23 axis plays a critical role in diabetes-associated vascular oxidative stress and altered insulin signaling. Targeting chemerin/chemerin receptor 23 may be an attractive strategy to improve insulin signaling and vascular function in obesity-associated diabetes. (AU)

• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 15/01630-3 - Role of chemerin/ChemR23 system on insulin signalling in adipocytes and arteries of db/db mice
• Grantee: Karla Bianca Neves
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 12/13144-8 - Effects of the adipokine Chemerin on the Responsiveness to Insulin Mesenteric Arteries of Mice
• Grantee: Karla Bianca Neves
• Support Opportunities: Scholarships in Brazil - Doctorate