Cyclooxygenase-2 in Endothelial and Vascular Smooth Muscle Cells Restrains Atherogenesis in Hyperlipidemic Mice

Author:

Tang Soon Yew1,Monslow James1,Todd Leslie1,Lawson John1,Puré Ellen1,FitzGerald Garret A.1

Affiliation:

1. From the Institute for Translational Medicine and Therapeutics (S.Y.T., J.M., J.L., G.A.F.) and Perelman School of Medicine, Department of Animal Biology, School of Veterinary Medicine (L.T., E.P.), University of Pennsylvania, Philadelphia.

Abstract

Background— Placebo-controlled trials of nonsteroidal anti-inflammatory drugs selective for inhibition of cyclooxygenase-2 (COX-2) reveal an emergent cardiovascular hazard in patients selected for low risk of heart disease. Postnatal global deletion of COX-2 accelerates atherogenesis in hyperlipidemic mice, a process delayed by selective enzyme deletion in macrophages. Methods and Results— In the present study, selective depletion of COX-2 in vascular smooth muscle cells and endothelial cells depressed biosynthesis of prostaglandin I 2 and prostaglandin E 2 , elevated blood pressure, and accelerated atherogenesis in Ldlr knockout mice. Deletion of COX-2 in vascular smooth muscle cells and endothelial cells coincided with an increase in COX-2 expression in lesional macrophages and increased biosynthesis of thromboxane. Increased accumulation of less organized intimal collagen, laminin, α-smooth muscle actin, and matrix-rich fibrosis was also apparent in lesions of the mutants. Conclusions— Although atherogenesis is accelerated in global COX-2 knockouts, consistent with evidence of risk transformation during chronic nonsteroidal anti-inflammatory drug administration, this masks the contrasting effects of enzyme depletion in macrophages versus vascular smooth muscle cells and endothelial cells. Targeting delivery of COX-2 inhibitors to macrophages may conserve their efficacy while limiting cardiovascular risk.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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