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Calcium phosphate crystals found in atherosclerotic plaques induce cytotoxic effects via loss of cellular calcium homeostasis.

Sharma, Kumar; Rietdorf, Katja; Proudfoot, Diane; McDonald, Fraser and Bootman, Martin D. (2016). Calcium phosphate crystals found in atherosclerotic plaques induce cytotoxic effects via loss of cellular calcium homeostasis. In: 14th International Meeting of the European Calcium Society, 25-29 September 2016, Valladolid, Spain.

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Abstract

Smooth muscle cells (SMCs) help to prevent atherosclerotic plaques from rupturing by synthesizing collagen that surrounds, and protects, the fibrous plaque cap. SMC death occurs within atherosclerotic plaques, contributing to plaque instability. Previous observations (1) suggest that calcium phosphate (CaP) crystals formed within a plaque are cytotoxic to SMCs and cause rapid necrosis that coincides with a loss of calcium homeostasis. In our study, A7r5 cells were exposed to 12.5 μg/ml of CaP crystals, and changes in intracellular calcium homeostasis were recorded for 45 minutes using the calcium indicator Fura-2. We observed that CaP crystals induced calcium oscillations followed by an irreversible calcium rise that culminated in cell death. Reducing sarco/endoplasmic reticulum calcium release by expression of a 5’-phosphatase enzyme, which rapidly metabolises IP3, significantly reduced the cytotoxicity of CaP crystals. Similarly, adding the SERCA pump inhibitor cyclopiazonic acid, preventing store-operated calcium release via addition of gadolinium, incubation with the lysosomal calcium release antagonist bafilomycin A1, or depolarising the mitochondria membrane potential with antimycin/oligomycin, also significantly reduced the cytotoxicity of CaP crystals. Expression of annexins, a familiy of cell membrane repair proteins, protected SMCs from CaP-induced cell death. Our data supports the hypothesis whereby endocytosis of CaP crystals, or CaP induced cell membrane rupture, leads to a rapid loss of calcium homeostasis and cell death. Attenuating calcium signalling, or enhancing cell membrane repair, can protect cells from the cytotoxic effects of CaP crystals.

Item Type: Conference or Workshop Item
Copyright Holders: 2016 The Authors
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Interdisciplinary Research Centre: Biomedical Research Network (BRN)
Health and Wellbeing PRA (Priority Research Area)
Related URLs:
Item ID: 47730
Depositing User: Katja Rietdorf
Date Deposited: 03 Nov 2016 09:00
Last Modified: 11 Sep 2017 15:32
URI: http://oro.open.ac.uk/id/eprint/47730
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