on April 25, 2002
Published online before print April 25, 2002, doi: 10.1161/01.ATV.0000019734.89917.35
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Submitted on February 15, 2002
Accepted on April 3, 2002
Cyclooxygenase-2--Dependent Prostacyclin Formation Is Regulated by Low Density Lipoprotein Cholesterol In Vitro
Layton Harris Smith ;
From the Departments of Pharmacology (L.H.S., D.E.V.) and Medicine (J.D.M., J.A.O., D.E.V.), Divisions of Clinical Pharmacology (O.B., J.D.M., J.O.A.), Cardiovascular Medicine (D.E.V.), and Nephrology (M.B.), Vanderbilt University Medical Center, and the Department of Veterans Affairs Medical Center, Nashville, Tenn.
* To whom correspondence should be addressed. E-mail: doug.vaughan{at}mcmail.vanderbilt.edu.
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 (PGI2) production. Human umbilical vein endothelial cells exposed to reduced concentrations of LDL demonstrated increased PGI2 production in a dose-dependent manner (from 0.75±0.2 to 2.6±0.2 ng/mL, P<0.0001). This alteration in PGI2 production did not result from LDL-induced changes in PGI2 synthase expression. However, selective inhibition of COX-2, but not COX-1, blocked PGI2 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 PGI2 production by 45.9% (from 0.55±0.09 to 0.25±0.08 ng/mL). Taken together, these observations indicate that endothelial PGI2 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.