(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
This article has been cited by other articles:
 |
|
 |
|
  J.-o Deguchi, H. Yamazaki, E. Aikawa, and M. Aikawa Chronic Hypoxia Activates the Akt and {beta}-Catenin Pathways in Human Macrophages Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1664 - 1670. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. de Nigris, S. Williams-Ignarro, V. Sica, L. O. Lerman, F. P. D'Armiento, R. E. Byrns, A. Casamassimi, D. Carpentiero, C. Schiano, D. Sumi, et al. Effects of a Pomegranate Fruit Extract rich in punicalagin on oxidation-sensitive genes and eNOS activity at sites of perturbed shear stress and atherogenesis Cardiovasc Res, January 15, 2007; 73(2): 414 - 423. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Napoli, L. O. Lerman, F. de Nigris, M. Gossl, M. L. Balestrieri, and A. Lerman Rethinking Primary Prevention of Atherosclerosis-Related Diseases Circulation, December 5, 2006; 114(23): 2517 - 2527. [Full Text] [PDF]
|
|
|
|
 |
|
 F. de Nigris, S. Williams-Ignarro, L. O. Lerman, E. Crimi, C. Botti, G. Mansueto, F. P. D'Armiento, G. De Rosa, V. Sica, L. J. Ignarro, et al. Beneficial effects of pomegranate juice on oxidation-sensitive genes and endothelial nitric oxide synthase activity at sites of perturbed shear stress PNAS, March 29, 2005; 102(13): 4896 - 4901. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. de Nigris, L. O. Lerman, S. W. Ignarro, G. Sica, A. Lerman, W. Palinski, L. J. Ignarro, and C. Napoli From the Cover: Beneficial effects of antioxidants and L-arginine on oxidation-sensitive gene expression and endothelial NO synthase activity at sites of disturbed shear stress PNAS, February 4, 2003; 100(3): 1420 - 1425. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. Schwenke, L. L. Rudel, M. G. Sorci-Thomas, and M. J. Thomas {alpha}-Tocopherol protects against diet induced atherosclerosis in New Zealand white rabbits J. Lipid Res., November 1, 2002; 43(11): 1927 - 1938. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Napoli, L. O. Lerman, F. de Nigris, J. Loscalzo, and L. J. Ignarro Glycoxidized low-density lipoprotein downregulates endothelial nitricoxide synthase in human coronary cells J. Am. Coll. Cardiol., October 16, 2002; 40(8): 1515 - 1522. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Napoli, E. Ackah, F. de Nigris, P. Del Soldato, F. P. D'Armiento, E. Crimi, M. Condorelli, and W. C. Sessa Chronic treatment with nitric oxide-releasing aspirin reduces plasma low-density lipoprotein oxidation and oxidative stress, arterial oxidation-specific epitopes, and atherogenesis in hypercholesterolemic mice PNAS, September 17, 2002; 99(19): 12467 - 12470. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. PALINSKI and C. NAPOLI The fetal origins of atherosclerosis: maternal hypercholesterolemia, and cholesterol-lowering or antioxidant treatment during pregnancy influence in utero programming and postnatal susceptibility to atherogenesis FASEB J, September 1, 2002; 16(11): 1348 - 1360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tanaga, H. Bujo, M. Inoue, K. Mikami, K. Kotani, K. Takahashi, T. Kanno, and Y. Saito Increased Circulating Malondialdehyde-Modified LDL Levels in Patients With Coronary Artery Diseases and Their Association With Peak Sizes of LDL Particles Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 662 - 666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Napoli, F. de Nigris, J. S. Welch, F. B. Calara, R. O. Stuart, C. K. Glass, and W. Palinski Maternal Hypercholesterolemia During Pregnancy Promotes Early Atherogenesis in LDL Receptor-Deficient Mice and Alters Aortic Gene Expression Determined by Microarray Circulation, March 19, 2002; 105(11): 1360 - 1367. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Liguori, P Abete, J.M Hayden, F Cacciatore, F Rengo, G Ambrosio, D Bonaduce, M Condorelli, P.D Reaven, and C Napoli Effect of glycaemic control and age on low-density lipoprotein susceptibility to oxidation in diabetes mellitus type 1 Eur. Heart J., November 2, 2001; 22(22): 2075 - 2084. [Abstract] [PDF]
|
|
|
|
|
|
G. CONDORELLI, J. K. AYCOCK, G. FRATI, and C. NAPOLI Mutated p21/WAF/CIP transgene overexpression reduces smooth muscle cell proliferation, macrophage deposition, oxidation-sensitive mechanisms, and restenosis in hypercholesterolemic apolipoprotein E knockout mice FASEB J, October 1, 2001; 15(12): 2162 - 2170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Napoli, G. Cirino, P. Del Soldato, R. Sorrentino, V. Sica, M. Condorelli, A. Pinto, and L. J. Ignarro Effects of nitric oxide-releasing aspirin versus aspirin on restenosis in hypercholesterolemic mice PNAS, February 27, 2001; 98(5): 2860 - 2864. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Napoli, J. L. Witztum, F. Calara, F. de Nigris, and W. Palinski Maternal Hypercholesterolemia Enhances Atherogenesis in Normocholesterolemic Rabbits, Which Is Inhibited by Antioxidant or Lipid-Lowering Intervention During Pregnancy : An Experimental Model of Atherogenic Mechanisms in Human Fetuses Circ. Res., November 10, 2000; 87(10): 946 - 952. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tanaga, H. Bujo, M. Inoue, K. Mikami, K. Kotani, K. Takahashi, T. Kanno, and Y. Saito Increased Circulating Malondialdehyde-Modified LDL Levels in Patients With Coronary Artery Diseases and Their Association With Peak Sizes of LDL Particles Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 662 - 666. [Abstract] [Full Text] [PDF]
|
|