title: Altered vascular smooth muscle function in the ApoE knockout mouse during the progression of atherosclerosis.
abstract: OBJECTIVE
  Relaxation of vascular smooth muscle (VSM) requires re-uptake of cytosolic Ca(2+) into the sarcoplasmic reticulum (SR) via the Sarco/Endoplasmic Reticulum Ca(2+) ATPase (SERCA), or extrusion via the Plasma Membrane Ca(2+) ATPase (PMCA) or sodium Ca(2+) 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 Ca(2+) handling processes within vascular smooth muscle cells were altered as atherosclerosis develops.
  
  
  METHODS
  Aortae from control and ApoE(-/-) mice were studied histologically, functionally and for protein expression levels of SERCA and PMCA. Ca(2+) responses were assessed in dissociated aortic smooth muscle cells in the presence and absence of extracellular Ca(2+).
  
  
  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 Ca(2+) [Ca(2+)]c in response to SERCA blockade were reduced, while SERCA-independent Ca(2+) clearance was faster compared to control.
  
  
  CONCLUSIONS
  As atherosclerosis develops in the ApoE(-/-) mouse, expression and function of Ca(2+) handling proteins are altered. Up-regulation of Ca(2+) removal via PMCA may offer a potential compensatory mechanism to help normalise the dysfunctional relaxation observed during disease progression.
authors.affiliation: Institute of Cardiovascular & Medical Sciences, University of Glasgow, G12 8QQ, UK. Electronic address: Marie-Ann.Ewart@glasgow.ac.uk.
authors.forename: Marie-Ann
authors.initials: MA
authors.lastname: Ewart
authors.affiliation: Institute of Cardiovascular & Medical Sciences, University of Glasgow, G12 8QQ, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Kennedy
authors.affiliation: Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK.
authors.forename: Debbi
authors.initials: D
authors.lastname: Macmillan
authors.affiliation: Institute of Cardiovascular & Medical Sciences, University of Glasgow, G12 8QQ, UK.
authors.forename: Abhirami L N
authors.initials: AL
authors.lastname: Raja
authors.affiliation: Institute of Cardiovascular & Medical Sciences, University of Glasgow, G12 8QQ, UK.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Watt
authors.affiliation: Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Currie
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000503:physiopathology*; D002118:Calcium / Q000502:physiology; D018450:Disease Progression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology*; D030421:Peroxynitrous Acid / Q000494:pharmacology; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000096:biosynthesis; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000096:biosynthesis
chemical_list: D001057:Apolipoproteins E; D030421:Peroxynitrous Acid; D053499:Plasma Membrane Calcium-Transporting ATPases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: Atherosclerosis; Ca(2+); PMCA; Peroxynitrite; SERCA