New mechanisms of LDL-cholesterol induced endothelial dysfunction; correction by statins.

High LDL-cholesterol is a risk factor for atherosclerosis and cardiovascular events. Dysfunction of the endothelium, e.g. the impairment of its capacity to produce nitric oxide (NO) is an early step in atherogenesis. We identified a mechanism of endothelial toxicity of LDL-cholesterol that alters the activity of the endothelial isoform of nitric oxide synthase (eNOS) in the absence of changes in its expression (abundance). This effect involves the transcriptional activation of the gene encoding caveolin-1, a structural protein of caveolae that acts as a negative allosteric regulator of eNOS. The effect is proportional to the increase in intracellular cholesterol that modulates caveolin-1 gene transcription, through the Sterol Regulatory Element Binding Protein (SREBP). Treatment of endothelial cells with statins (inhibitors of cholesterol synthesis) abrogates caveolin-1 upregulation and restores eNOS activity in vitro and in vivo in genetically apoE-deficient, hypercholesterolemic mice.