Evidence for oxidative activation of c-Myc-dependent nuclear signaling in human coronary smooth muscle cells and in early lesions of Watanabe heritable hyperlipidemic rabbits: protective effects of vitamin E.
BACKGROUND
Oxidized LDL (oxLDL) promotes atherogenesis, and antioxidants reduce lesions in experimental models. OxLDL-mediated effects on c-Myc are poorly characterized, and those on c-Myc nuclear pathways are completely unknown. c-Myc stimulates smooth muscle cell (SMC) proliferation and could be involved in atherosclerosis. We investigated the early effects of oxLDL and alpha-tocopherol on c-Myc, its binding partner Max, and the carboxy-terminal domain-binding factors activator protein-2 and elongation 2 factor in human coronary SMCs. We also investigated whether 9-week treatment of Watanabe heritable hyperlipidemic (WHHL) rabbits with diet-enriched alpha-tocopherol reduces c-Myc expression and oxLDL in the left coronary artery.


RESULTS
OxLDL enhanced c-Myc/Max expression and transcription by cotransfection assay and the nuclear activities of E2F and activator protein-2 by binding shift and supershift in coronary SMCs. alpha-Tocopherol significantly reduced these molecular events. Furthermore, alpha-tocopherol reduced early lesions, SMC density, and the immunohistochemical presence of c-Myc, which colocalized with oxLDL/foam cells in the coronaries of WHHL rabbits.


CONCLUSIONS
We provide the first evidence that oxLDL and alpha-tocopherol may influence c-Myc activation and several c-Myc-dependent signaling pathways in human coronary SMCs. The observation that in vivo, an antioxidant reduces both c-Myc and oxLDL in early coronary lesions of rabbits is consistent with, but does not prove, the hypothesis that c-Myc-dependent factors activated by oxidative processes contribute to atherogenesis and coronary heart disease.
de Nigris
F
F
Department of Medicine, Federico II University of Naples, Naples, Italy.
Youssef
T
T
Ciafré
S
S
Franconi
F
F
Anania
V
V
Condorelli
G
G
Palinski
W
W
Napoli
C
C
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D050684:E2F Transcription Factors; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism* / Q000502:physiology; D011817:Rabbits; D056465:Retinoblastoma-Binding Protein 1; D015398:Signal Transduction; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology* / Q000627:therapeutic use
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; C436492:KLF12 protein, human; D051741:Kruppel-Like Transcription Factors; D008077:Lipoproteins, LDL; C499330:MAX protein, human; C067850:Myc associated factor X; D016271:Proto-Oncogene Proteins c-myc; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; C099252:oxidized low density lipoprotein; D014810:Vitamin E