Impact of oxidized low density lipoprotein on vascular cells

Abstract 

Oxidized LDL (OxLDL) is a proatherogenic lipoprotein, accumulating in the vascular wall and contributing to the pathogenesis of vascular dysfunction early in the development of atherosclerosis. Enhanced serum levels of OxLDL, as well as antibodies against its epitopes, are predictive for endothelial dysfunction and coronary heart disease. While enhanced oxidative stress is one factor triggering formation of OxLDL, OxLDL itself has been identified as a potent stimulus for vascular oxygen radical formation, causing a vicious circle. OxLDL-induced O₂⁻ formation, largely through activation of NADPH oxidase, but also through uncoupling of endothelial NO-synthase and through direct O₂⁻ release, leads to endothelial dysfunction. Furthermore, OxLDL-induced O₂⁻ formation has a strong impact on tissue remodeling, resulting in either cell growth – proliferation or hyperplasia – or apoptotic cell death. The effect of OxLDL on cell cycle regulation is mediated by activation of the small GTPase RhoA and consequent regulation of p27^KIP1, a key enzyme of the cell cycle. In addition, OxLDL-induced activation of RhoA sensitizes the contractile apparatus of the vessel wall, enhancing the contractile tonus and favoring vasospasm. Thus, through a variety of mechanisms, OxLDL importantly contributes to vascular dysfunction and remodeling.

Keywords: Oxidative stress, NAD(P)H-oxidase, NO-synthase, Atherosclerosis, Lipoprotein, Proliferation, GTPase, RhoA