期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
卷 1823, 期 2, 页码 420-429出版社
ELSEVIER
DOI: 10.1016/j.bbamcr.2011.09.019
关键词
Human monocyte derived macrophage; Hypochlorous acid; Calcium ion; Mitochondrial membrane potential; Calpain; Lysosomal stability
资金
- National Heart Foundation of New Zealand
- School of Biological Sciences, University of Canterbury
The abundance of dead macrophages in close proximity to HOCl-modified proteins in advanced atherosclerotic plaques implicates HOCl in the killing of macrophages and the formation of the necrotic core region. The mechanism of HOCl mediated death of macrophages was unknown, so using human monocyte derived macrophages (HMDM) we here have shown that HOCl causes a rapid necrotic cell death characterized by loss of MTT reduction, cellular ATP and cell lysis without caspase-3 activation in HMDM cells. The HOCl causes a rise in cytosolic calcium level via the plasma membrane L- and T-type calcium channels and endoplasmic reticulum RyR channel. Blocking of the calcium channels or the addition of calpain inhibitors prevents the HOCl mediated loss of mitochondrial potential, lysosome failure and HMDM cell death. Blocking MPT-pore formation with cyclosporin A also prevents the loss of mitochondrial membrane potential, lysosomal destabilization and HMDM cell death. Blocking the calcium mitochondrial uniporter with ruthenium red also blocks the loss of mitochondrial potential but only at high concentrations. HOCl appears to cause HMDM cell death through destabilization of cytosolic calcium control resulting in the failure of both the mitochondria and lysosomes. (C) 2011 Elsevier B.V. All rights reserved.
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