title: Mildly oxidized low density lipoprotein activates multiple apoptotic signaling pathways in human coronary cells.
abstract: Apoptosis of arterial cells induced by oxidized low density lipoproteins (OxLDL) is thought to contribute to the progression of atherosclerosis. However, most data on apoptotic effects and mechanisms of OxLDL were obtained with extensively oxidized LDL unlikely to occur in early stages of atherosclerotic lesions. We now demonstrate that mildly oxidized LDL generated by incubation with oxygen radical-producing xanthine/xanthine oxidase (X/XO) induces apoptosis in primary cultures of human coronary endothelial and SMC, as determined by TUNEL technique, DNA laddering, and FACS analysis. Apoptosis was markedly reduced when X/XO-LDL was generated in the presence of different oxygen radical scavengers. Apoptotic signals were mediated by intramembrane domains of both Fas and tumor necrosis factor (TNF) receptors I and II. Blocking of Fas ligand (FasL) reduced apoptosis by 50% and simultaneous blocking of FasL and TNF receptors by 70%. Activation of apoptotic receptors was accompanied by an increase of proapoptotic and a decrease in antiapoptotic proteins of the Bcl-2 family and resulted in marked activation of class I and II caspases. Mildly oxidized LDL also activated MAP and Jun kinases and increased p53 and other transcription factors (ATF-2, ELK-1, CREB, AP-1). Inhibitors of Map and Jun kinase significantly reduced apoptosis. Our results provide the first evidence that OxLDL-induced apoptosis involves TNF receptors and Jun activation. More important, they demonstrate that even mildly oxidized LDL formed in atherosclerotic lesions may activate a broad cascade of oxygen radical-sensitive signaling pathways affecting apoptosis and other processes influencing the evolution of plaques. Thus, we suggest that extensive oxidative modifications of LDL are not necessary to influence signal transduction and transcription in vivo.
authors.affiliation: Department of Medicine-0682, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: C
authors.initials: C
authors.lastname: Napoli
authors.forename: O
authors.initials: O
authors.lastname: Quehenberger
authors.forename: F
authors.initials: F
authors.lastname: De Nigris
authors.forename: P
authors.initials: P
authors.lastname: Abete
authors.forename: C K
authors.initials: CK
authors.lastname: Glass
authors.forename: W
authors.initials: W
authors.lastname: Palinski
mesh_terms: D017209:Apoptosis; D001161:Arteriosclerosis / Q000209:etiology; D020169:Caspases / Q000378:metabolism; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects*; D004789:Enzyme Activation; D019254:Genes, bcl-2; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D019014:fas Receptor
chemical_list: D008077:Lipoproteins, LDL; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D018808:Transcription Factor AP-1; D019014:fas Receptor; C099252:oxidized low density lipoprotein; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases