Published online before print July 31, 2008, doi: 10.1161/CIRCRESAHA.108.181305
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Submitted on June 13, 2008
Revised on July 21, 2008
Accepted on July 22, 2008
Calcium Phosphate Crystals Induce Cell Death in Human Vascular Smooth Muscle Cells. A Potential Mechanism in Atherosclerotic Plaque Destabilization
Alexandra E. Ewence ;
From the Division of Cardiovascular Medicine (A.E.E., D.P.), University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; the Laboratory of Molecular Signalling (M.B., H.L.R.), The Babraham Institute, Babraham, Cambridge, UK; the Department of Anatomy (J.N.S.), Multi-Imaging Centre, University of Cambridge, Cambridge, UK; the Department of Clinical Pharmacology (G.M.), Royal College of Surgeons in Ireland, Dublin, UK; Inorganic Chemistry (M.E., M.N.), University of Duisburg-Essen, Essen, Germany; and Kings College London (C.M.S.), Cardiovascular Division, James Black Centre, London, UK; and the Department of Pharmacology (H.L.R.), University of Cambridge, UK.
* To whom correspondence should be addressed. E-mail: dianeproudfoot{at}gmail.com.
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 µm 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.
Key words: apoptosis • atherosclerosis • calcification • vascular smooth muscle cells
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