Two distinct calcium-dependent mitochondrial pathways are involved in oxidized LDL-induced apoptosis.

Abstract

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.

• Authors: Cécile Vindis, Meyer Elbaz, Isabelle Escargueil-Blanc, Nathalie Augé, Aurelia Heniquez, Jean-Claude Thiers, Anne Nègre-Salvayre, Robert Salvayre
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 25 Issue 3 Pg. 639-45 (Mar 2005) ISSN: 1524-4636 [Electronic] United States
• PMID: 15618541 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AIFM1 protein, human
• Apoptosis Inducing Factor
• BH3 Interacting Domain Death Agonist Protein
• BID protein, human
• Carrier Proteins
• Caspase Inhibitors
• Cysteine Proteinase Inhibitors
• Flavoproteins
• Immunosuppressive Agents
• Lipoproteins, LDL
• Membrane Proteins
• oxidized low density lipoprotein
• Cyclosporine
• Cytochromes c
• CASP3 protein, human
• Calpain
• Caspase 3
• Caspases
• Calcium
• Tacrolimus

Topics

• Apoptosis (drug effects, physiology)
• Apoptosis Inducing Factor
• Arteriosclerosis (metabolism, pathology)
• BH3 Interacting Domain Death Agonist Protein
• Calcium (metabolism)
• Calpain (metabolism)
• Carrier Proteins (metabolism)
• Caspase 3
• Caspase Inhibitors
• Caspases (metabolism)
• Cells, Cultured
• Cyclosporine (pharmacology)
• Cysteine Proteinase Inhibitors (pharmacology)
• Cytochromes c (metabolism)
• Endothelium, Vascular (cytology, metabolism)
• Flavoproteins (metabolism)
• Humans
• Immunosuppressive Agents (pharmacology)
• Lipoproteins, LDL (metabolism)
• Membrane Proteins (metabolism)
• Microcirculation
• Mitochondria (metabolism)
• Tacrolimus (pharmacology)