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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:639.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Two Distinct Calcium-Dependent Mitochondrial Pathways Are Involved in Oxidized LDL-Induced Apoptosis

Cécile Vindis; Meyer Elbaz; Isabelle Escargueil-Blanc; Nathalie Augé; Aurelia Heniquez; Jean-Claude Thiers; Anne Nègre-Salvayre; Robert Salvayre

From INSERM U-466 and the Department of Biochemistry and Molecular Biology, IFR-31, CHU Rangueil, Toulouse, France.

Correspondence to Prof R. Salvayre, Biochimie, Inserm U-466, IFR-31, CHU Rangueil 1, avenue Jean Poulhès, TSA-0032, 31059 Toulouse Cedex 9, France. 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.

We investigated the potential relationship between calcium signaling, proteolytic cascade, and mitochondrial apoptotic pathways involved in oxidized low-density lipoprotein (oxLDL)-induced apoptosis. OxLDL-induced apoptosis was mediated by 2 distinct mitochondrial pathways, one involving calcium/calpain/mitochondrial permeability transition pore/cytochrome C/caspase-3 and the other calcium-dependent release of apoptosis inducing factor.

Key Words: calpain • caspase • mitochondria • apoptosis-inducing factor • oxidized low-density lipoprotein • atherosclerosis

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