on December 23, 2004
Published online before print December 23, 2004, doi: 10.1161/01.ATV.0000154359.60886.33
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Submitted on April 7, 2004
Accepted on December 11, 2004
Two Distinct Calcium-Dependent Mitochondrial Pathways Are Involved in Oxidized LDL-Induced Apoptosis
Cécile Vindis ;
From INSERM U-466 and the Department of Biochemistry and Molecular Biology, IFR-31, CHU Rangueil, Toulouse, France.
* To whom correspondence should be addressed. E-mail: salvayre{at}toulouse.inserm.fr.
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.
Key words: calpain • caspase • mitochondria • apoptosis-inducing factor • oxidized low-density lipoprotein • atherosclerosis
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