Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 25, Issue 3, Pages 639-645Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.ATV.0000154359.60886.33
Keywords
calpain; caspase; mitochondria; apoptosis-inducing factor; oxidized low-density lipoprotein; atherosclerosis
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Objective - Oxidized low-density lipoprotein (oxLDL) - induced apoptosis of vascular endothelial cells may contribute to plaque erosion and rupture. We aimed to clarify the relationship between the oxLDL- induced calcium signal and induction of apoptotic pathways. Methods and Results - Apoptosis was evaluated by biochemical methods, including studies of enzyme activities, protein processing, release of proapoptotic factors, chromatin cleavage, and especially by morphological methods that evaluate apoptosis/ necrosis by SYTO- 13/ propidium iodide fluorescent labeling. The oxLDL- induced sustained calcium rise activated 2 distinct calcium- dependent mitochondrial apoptotic pathways in human microvascular endothelial cells. OxLDLs induced calpain activation and subsequent Bid cleavage and cytochrome C release, which were blocked by calpeptin. Cyclosporin- A inhibited cytochrome C release, possibly by inhibiting the opening of the mitochondrial permeability transition pore ( mPTP). Calcineurin, another cyclosporin- sensitive step, was not implicated, because oxLDLs inhibited calcineurin and FK- 506 treatment was ineffective. Cytochrome C release in turn induced caspase- 3 activation. In addition, oxLDLs triggered release and nuclear translocation of mitochondrial apoptosis-inducing factor through a mechanism dependent on calcium but independent of calpains, mPTP, and caspases. Conclusions - OxLDL-induced apoptosis involves 2 distinct calcium- dependent pathways, the first mediated by calpain/ mPTP/cytochrome C/caspase-3 and the second mediated by apoptosis-inducing factor, which is cyclosporin- insensitive and caspase- independent.
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