Changes in IP3 receptor expression and function in aortic smooth muscle of atherosclerotic mice

Ewart, M.-A., Ugusman, A., Vishwanath, A., Almabrouk, T. A.M., Alganga, H. S.F., Katwan, O. J., Hubanova, P., Currie, S. and Kennedy, S. (2017) Changes in IP3 receptor expression and function in aortic smooth muscle of atherosclerotic mice. Journal of Vascular Research, 54(2), pp. 68-78. (doi: 10.1159/000461581) (PMID:28365690) (PMCID:PMC5804831)

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Abstract

Peroxynitrite is an endothelium-independent vasodilator that induces relaxation via membrane hyperpolarization. The activation of IP3 receptors triggers the opening of potassium channels and hyperpolarization. Previously we found that relaxation to peroxynitrite was maintained during the development of atherosclerosis due to changes in the expression of calcium-regulatory proteins. In this study we investigated: (1) the mechanism of peroxynitrite-induced relaxation in the mouse aorta, (2) the effect of atherosclerosis on relaxation to peroxynitrite and other vasodilators, and (3) the effect of atherosclerosis on the expression and function of the IP3 receptor. Aortic function was studied using wire myography, and atherosclerosis was induced by fat-feeding ApoE-/- mice. The expression of IP3 receptors was studied using Western blotting and immunohistochemistry. Relaxation to peroxynitrite was attenuated by the IP3 antagonists 2-APB and xestospongin C and also the Kv channel blocker 4-aminopyridine (4-AP). Atherosclerosis attenuated vasodilation to cromakalim and the AMPK activator A769662 but not peroxynitrite. Relaxation was attenuated to a greater extent by 2-APB in atherosclerotic aortae despite the reduced expression of IP3 receptors. 4-AP was less effective in ApoE-/- mice fat-fed for 4 months. Peroxynitrite relaxation involves an IP3-induced calcium release and KV channel activation. This mechanism becomes less important as atherosclerosis develops, and relaxation to peroxynitrite may be maintained by increased calcium extrusion.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:ALGANGA, Husam S F and Kennedy, Professor Simon and Ewart, Dr Marie-Ann
Authors: Ewart, M.-A., Ugusman, A., Vishwanath, A., Almabrouk, T. A.M., Alganga, H. S.F., Katwan, O. J., Hubanova, P., Currie, S., and Kennedy, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Journal of Vascular Research
Publisher:Karger Publishers
ISSN:1018-1172
ISSN (Online):1423-0135
Published Online:01 April 2017

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
447641Modulation of calcium handling mechanisms in healthy and atherosclerotic vascular smooth muscleSimon KennedyBritish Heart Foundation (BHF)PG/07/012/22342RI CARDIOVASCULAR & MEDICAL SCIENCES