Cyclooxygenase-2–Dependent Prostacyclin Formation Is Regulated by Low Density Lipoprotein Cholesterol In Vitro

Abstract

Reduction of plasma low density lipoprotein (LDL) levels is associated with a reduced risk of myocardial infarction, stroke, and death. Some of this clinical benefit may be derived from an improvement in endothelium-dependent vasodilation. In the present study, we examined the effects of LDL reduction on cyclooxygenase (COX) activity and prostacyclin (PGI 2 ) production. Human umbilical vein endothelial cells exposed to reduced concentrations of LDL demonstrated increased PGI 2 production in a dose-dependent manner (from 0.75±0.2 to 2.6±0.2 ng/mL, P <0.0001). This alteration in PGI 2 production did not result from LDL-induced changes in PGI 2 synthase expression. However, selective inhibition of COX-2, but not COX-1, blocked PGI 2 production under low cholesterol conditions. Addition of exogenous cholesterol induces dose-dependent reductions in endothelial COX-2 expression as measured by reverse transcription–polymerase chain reaction and by Western blotting. Pretreatment of cells with actinomycin D, a transcription inhibitor, reduced COX-2–derived PGI 2 production by 45.9% (from 0.55±0.09 to 0.25±0.08 ng/mL). Taken together, these observations indicate that endothelial PGI 2 production is regulated by cholesterol at the transcriptional level and that cholesterol-sensitive transcriptional pathways that regulate COX-2 expression are present in vascular tissue.