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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:983.)
© 2002 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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

Layton Harris Smith; Olivier Boutaud; Matthew Breyer; Jason D. Morrow; John A. Oates; Douglas E. Vaughan

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.

Correspondence to Douglas E. Vaughan, MD, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 2220 Pierce Ave PRB 312, Nashville, TN 37232. 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.

Key Words: cyclooxygenase • prostacyclin • cholesterol • LDL • endothelial

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