Oxidized LDLs alter the activity of the ubiquitin-proteasome pathway: potential role in oxidized LDL-induced apoptosis.
Oxidized low-density lipoproteins (oxLDL) play a role in the genesis of atherosclerosis. OxLDL are able to induce apoptosis of vascular cells, which is potentially involved in the formation of the necrotic center of atherosclerotic lesions, plaque rupture, and subsequent thrombotic events. Because oxLDL may induce structural modifications of cell protein and altered proteins may impair cell viability, the present work aimed to evaluate the extent of protein alterations, the degradation of modified proteins through the ubiquitin-proteasome system (a major degradative pathway for altered and oxidatively modified proteins) and their role during apoptosis induced by oxLDL. This paper reports the following: 1) oxLDL induce derivatization of cell proteins by 4-hydroxynonenal (4-HNE) and ubiquitination. 2) Toxic concentrations of oxLDL elicit a biphasic effect on proteasome activity. An early and transient activation of endogenous proteolysis is followed rapidly by a subsequent decay (resulting probably from the 26S proteasome inhibition) and followed later by the inhibition of the 20S proteasome (as assessed by inhibition of sLLVY-MCA hydrolysis). 3) Specific inhibitors of proteasome (lactacystin and proteasome inhibitor I) potentiated considerably the toxicity of oxLDL (nontoxic doses of oxLDL became severely toxic). The defect of the ubiquitination pathway (in temperature-sensitive mutants) also potentiated the toxicity of oxLDL. This suggests that the ubiquitin-proteasome pathway plays a role in the cellular defenses against oxLDL-induced toxicity. 4) Dinitrophenylhydrazine (DNPH), an aldehyde reagent, prevented both the oxLDL-induced derivatization of cell proteins and subsequent cytotoxicity. Altogether, the reported data suggest that both derivatization of cell proteins (by 4-HNE and other oxidized lipids) and inhibition of the proteasome pathway are involved in the mechanism of oxLDL-induced apoptosis.
Vieira
O
O
INSERM U.466, Biochemistry Department, University Paul Sabatier, Toulouse, France.
Escargueil-Blanc
I
I
Jürgens
G
G
Borner
C
C
Almeida
L
L
Salvayre
R
R
Nègre-Salvayre
A
A
D016475:3T3 Cells; D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D001055:Apolipoproteins B / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004730:Endothelium, Vascular; D006801:Humans; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000502:physiology / Q000633:toxicity*; D051379:Mice; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D014452:Ubiquitins / Q000378:metabolism*
D000447:Aldehydes; D001055:Apolipoproteins B; D015853:Cysteine Proteinase Inhibitors; D008077:Lipoproteins, LDL; D009097:Multienzyme Complexes; D014452:Ubiquitins; C099252:oxidized low density lipoprotein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C027576:4-hydroxy-2-nonenal