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 re duce lesions in experimental models. OxLDL-mediated effects on c-Myc are po orly characterized, and those on c-Myc nuclear pathways are completely unkn own. c-Myc stimulates smooth muscle cell (SMC) proliferation and could be i nvolved in atherosclerosis. We investigated the early effects of oxLDL and alpha -tocopherol on c-Myc, its binding partner Max, and the carboxy-termin al domain-binding factors activator protein-2 and elongation 2 factor in hu man coronary SMCs, We also investigated whether 9-week treatment of Watanab e heritable hyperlipidemic (WHHL) rabbits with diet-enriched alpha -tocophe rol reduces c-Myc expression and oxLDL in the left coronary artery. Methods and Results-oxLDL enhanced c-Myc/Max expression and transcription b y cotransfection assay and the nuclear activities of E2F and activator prot ein-2 by binding shift and supershift in coronary SMCs. alpha -Tocopherol s ignificantly reduced these molecular events. Furthermore, alpha -tocopherol reduced early lesions, SMC density, and the immunohistochemical presence o f 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 pathwa ys in human coronary SMCs. The observation that in vivo, an antioxidant red uces both c-Myc and oxLDL in early coronary lesions of rabbits is consisten t with, but does not prove, the hypothesis that c-Myc-dependent factors act ivated by oxidative processes contribute to atherogenesis and coronary hear t disease.