Oxidized low density lipoprotein induces the cyclin-dependent kinase inhibitor p21waf1 and the tumor suppressor Rb

Oxidized low density lipoprotein (OxLDL) is known to be cytotoxic towards different cell types of the arterial wall, leading to progression of an atherosclerotic plaque. We previously reported that OxLDL activates the tumor suppressor p53 in human fibroblasts [Biochem. Biophys. Res. Commun. 276 (2000) 718]. In the present work, we demonstrate that OxLDL increased intracellular levels of the kinase inhibitor p21(waf1) (p21) and of the tumor suppressor Rb. Concomitantly, level of the hypophosphorylated active form of Rb (HypoP-Rb) was also enhanced. Cycloheximide prevented the OxLDL-induced increase in p21, Rb, and HypoP-Rb, whereas okadaic acid had no effect. This increase was also prevented by the antioxidant vitamin E. In addition, the lipid extract of OxLDL, which includes the lipid peroxidation products, reproduced the action of the OxLDL particle itself. OxLDL and its lipid extract induced an oxidative stress, as assessed by the intracellular levels of reactive oxygen species and lipid peroxidation products. Finally, OxLDL induced a dose-dependent inhibition of DNA synthesis as assessed by thymidine incorporation. These results demonstrate that OxLDL or its lipid peroxidation products, by generation of an oxidative stress, enhances the expression of p21 and Rb genes, leading to an accumulation of the Hypo-P active form of the tumor suppressor Rb. This phenomenon is in accordance with the fact that p21 is a mediator of p53-dependent cell-cycle arrest in G1 and is most probably involved in the cytotoxicity of OxLDL. (C) 2002 Elsevier Science (USA). All rights reserved.