title: Cyclosporin A inhibits apoptosis of human endothelial cells by preventing release of cytochrome C from mitochondria.
abstract: BACKGROUND
  Several experimental and clinical studies suggest that cyclosporin A (CSA) treatment reduces transplant atherosclerosis. Because oxidized LDL (oxLDL) is believed to play a key role in the development of atherogenesis, causing injury to the endothelium, and has been shown to induce apoptosis of endothelial cells, we investigated whether CSA inhibits oxLDL-induced apoptosis.
  
  
  RESULTS
  Apoptosis was induced in human umbilical venous endothelial cells (HUVECs) by incubation of 10 microg/mL oxLDL for 18 hours. Coincubation with CSA dose dependently decreased oxLDL-induced apoptosis, with a maximal effect at 10 micromol/L. In addition, tumor necrosis factor-alpha- and angiotensin II-induced apoptosis was significantly prevented by CSA treatment, suggesting a general apoptosis-suppressive effect of CSA. CSA has been shown to inhibit disruption of the mitochondrial membrane function, which plays a key role in apoptosis induction. Indeed, oxLDL treatment triggered the release of cytochrome C from the mitochondria into the cytosol, indicating disturbance of the mitochondrial membrane. CSA (10 micromol/L) completely inhibited the oxLDL-induced release of cytochrome C. Moreover, tumor necrosis factor-alpha- and angiotensin II-induced cytochrome C release was prevented by CSA treatment.
  
  
  CONCLUSIONS
  OxLDL induces dysfunction of the mitochondrial membrane, leading to cytochrome C release into the cytosol, and thereby stimulates apoptosis of human endothelial cells. Apoptosis suppression by CSA correlates with the prevention of mitochondrial dysfunction and thus indicates the importance of mitochondrial destabilization in oxLDL-induced apoptosis signaling. The inhibition of apoptosis by CSA might preserve the function of the endothelium and may at least in part contribute to the antiatherogenic effects of CSA in transplant atherosclerosis.
authors.affiliation: Department of Internal Medicine, Division of Cardiology, University of Frankfurt, Germany.
authors.forename: D H
authors.initials: DH
authors.lastname: Walter
authors.forename: J
authors.initials: J
authors.lastname: Haendeler
authors.forename: J
authors.initials: J
authors.lastname: Galle
authors.forename: A M
authors.initials: AM
authors.lastname: Zeiher
authors.forename: S
authors.initials: S
authors.lastname: Dimmeler
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001161:Arteriosclerosis / Q000188:drug therapy*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use; D003574:Cytochrome c Group / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors; D008928:Mitochondria / Q000187:drug effects*; D010539:Permeability / Q000187:drug effects
chemical_list: D003574:Cytochrome c Group; D007166:Immunosuppressive Agents; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D016572:Cyclosporine