title: Calcium phosphate crystals induce cell death in human vascular smooth muscle cells: a potential mechanism in atherosclerotic plaque destabilization.
abstract: Vascular calcification is associated with an increased risk of myocardial infarction; however, the mechanisms linking these 2 processes are unknown. Studies in macrophages have suggested that calcium phosphate crystals induce the release of proinflammatory cytokines; however, no studies have been performed on the effects of calcium phosphate crystals on vascular smooth muscle cell function. In the present study, we found that calcium phosphate crystals induced cell death in human aortic vascular smooth muscle cells with their potency depending on their size and composition. Calcium phosphate crystals of approximately 1 microm or less in diameter caused rapid rises in intracellular calcium concentration, an effect that was inhibited by the lysosomal proton pump inhibitor, bafilomycin A1. Bafilomycin A1 also blocked vascular smooth muscle cell death suggesting that crystal dissolution in lysosomes leads to an increase in intracellular calcium levels and subsequent cell death. These studies give novel insights into the bioactivity of calcified deposits and suggest that small calcium phosphate crystals could destabilize atherosclerotic plaques by initiating inflammation and by causing vascular smooth muscle cell death.
authors.affiliation: Division of Cardiovascular Medicine, University of Cambridge, ACCI Building, Level 6, Box 110, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Ewence
authors.forename: Martin
authors.initials: M
authors.lastname: Bootman
authors.forename: H Llewelyn
authors.initials: HL
authors.lastname: Roderick
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Skepper
authors.forename: Geraldine
authors.initials: G
authors.lastname: McCarthy
authors.forename: Matthias
authors.initials: M
authors.lastname: Epple
authors.forename: Markus
authors.initials: M
authors.lastname: Neumann
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Shanahan
authors.forename: Diane
authors.initials: D
authors.lastname: Proudfoot
mesh_terms: D017209:Apoptosis; D002114:Calcinosis / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D002130:Calcium Phosphates / Q000737:chemistry* / Q000493:pharmacokinetics; D002339:Carotid Arteries / Q000737:chemistry* / Q000473:pathology; D002340:Carotid Artery Diseases / Q000473:pathology*; D002452:Cell Count; D002470:Cell Survival; D003460:Crystallization; D004691:Endarterectomy; D005260:Female; D006801:Humans; D008297:Male; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000473:pathology / Q000648:ultrastructure; D032389:Myocytes, Smooth Muscle / Q000737:chemistry* / Q000473:pathology / Q000648:ultrastructure; D053758:Nanoparticles
chemical_list: D002130:Calcium Phosphates; C020243:calcium phosphate; D002118:Calcium