Altered vascular smooth muscle function in the ApoE knockout mouse during the progression of atherosclerosis

Ewart, M.-A., Kennedy, S. , MacMillan, D., Raja, A. L.N., Watt, I. M. and Currie, S. (2014) Altered vascular smooth muscle function in the ApoE knockout mouse during the progression of atherosclerosis. Atherosclerosis, 234(1), pp. 154-161. (doi: 10.1016/j.atherosclerosis.2014.02.014)

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Abstract

Objectives: Relaxation of vascular smooth muscle (VSM) requires re-uptake of cytosolic Ca2+ into the sarcoplasmic reticulum (SR) via the Sarco/Endoplasmic Reticulum Ca2+ ATPase (SERCA), or extrusion via the Plasma Membrane Ca2+ ATPase (PMCA) or sodium Ca2+ exchanger (NCX). Peroxynitrite, a reactive species formed in vascular inflammatory diseases, upregulates SERCA activity to induce relaxation but, chronically, can contribute to atherogenesis and altered vascular function by escalating endoplasmic reticulum stress. Our objectives were to determine if peroxynitrite-induced relaxation and Ca2+ handling processes within vascular smooth muscle cells were altered as atherosclerosis develops.<p></p> Methods: Aortae from control and ApoE−/− mice were studied histologically, functionally and for protein expression levels of SERCA and PMCA. Ca2+ responses were assessed in dissociated aortic smooth muscle cells in the presence and absence of extracellular Ca2+.<p></p> Results: Relaxation to peroxynitrite was concentration-dependent and endothelium-independent. The abilities of the SERCA blocker thapsigargin and the PMCA inhibitor carboxyeosin to block this relaxation were altered during fat feeding and plaque progression. SERCA levels were progressively reduced, while PMCA expression was upregulated. In ApoE−/− VSM cells, increases in cytosolic Ca2+ [Ca2+]c in response to SERCA blockade were reduced, while SERCA-independent Ca2+ clearance was faster compared to control.<p></p> Conclusion: As atherosclerosis develops in the ApoE−/− mouse, expression and function of Ca2+ handling proteins are altered. Up-regulation of Ca2+ removal via PMCA may offer a potential compensatory mechanism to help normalise the dysfunctional relaxation observed during disease progression.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Watt, Mr Ian and Kennedy, Professor Simon and Ewart, Dr Marie-Ann
Authors: Ewart, M.-A., Kennedy, S., MacMillan, D., Raja, A. L.N., Watt, I. M., and Currie, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Atherosclerosis
Publisher:Elsevier Ireland Ltd.
ISSN:0021-9150
ISSN (Online):1879-1484
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in Atherosclerosis 234(1):154-161
Publisher Policy:Reproduced under a Creative Commons License

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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