(Circulation. 2000;102:2111.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
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
From the Department of Medicine, Federico II University of Naples (F.d.N., C.N.), Naples, Italy; the Department of Pharmacology, University of Sassari (F.F., V.A.), Sassari, Italy; the Department of Cardiology–S. Donato, University of Milan (T.Y.), Milan, Italy; the Department of Biochemistry, II University of Rome (S.C.), Rome, Italy; Kimmel Cancer Center, Thomas Jefferson University (G.C.), Philadelphia, Pa; and the Department of Medicine, UCSD (W.P., C.N.), San Diego, Calif.
Correspondence to Claudio Napoli, MD, FACA, Medicine-Via B. Falcomata’ 5, 80128 Naples, Italy ( e-mail claunap{at}tin.it) or the Department of Medicine-0682, University of California at San Diego, 9500 Gilman Dr, San Diego, CA 92093 (
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 
-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 -tocopherol reduces c-Myc expression and
oxLDL in the left coronary artery.
Methods and 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. -Tocopherol significantly reduced
these molecular events. Furthermore, -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
-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.
Key Words: lipoproteins • coronary disease • antioxidants • atherosclerosis
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