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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

De Nigris, Filomena and Tammam, Youssef and Ciafré, Silvia Anna and Franconi, Flavia and Anania, Vittorio Domenico and Condorelli, Gianluigi and Palinski, Wulf and Napoli, Claudio (2000) 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. Circulation, Vol. 102 (17), p. 2111-2117. eISSN 1524-4539. Article.

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Abstract

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 α-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 α-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. a-Tocopherol significantly reduced these molecular events. Furthermore, a-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 a-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.

Item Type:Article
ID Code:3829
Status:Published
Refereed:Yes
Uncontrolled Keywords:Lipoproteins, coronary disease, antioxidants, atherosclerosis
Subjects:Area 05 - Scienze biologiche > BIO/14 Farmacologia
Area 07 - Scienze agrarie e veterinarie > VET/07 Farmacologia e tossicologia veterinaria
Divisions:001 Università di Sassari > 01 Dipartimenti > Biologia animale
001 Università di Sassari > 01 Dipartimenti > Scienze del farmaco
Publisher:Lippincott Williams & Wilkins
eISSN:1524-4539
Deposited On:13 May 2010 10:24

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