PPAR activators and COX inhibitors selectively block cytokine-induced COX-2 expression and activity in human aortic smooth muscle cells

Abstract

Atherosclerotic complications are related to the unstable character of the plaque rather than its volume. Vulnerable plaques often contain a large lipid core, a reduced content of smooth muscle cells (SMCs), and an accumulation of inflammatory cells. Regulation of this inflammatory response is an essential element in chronic inflammatory diseases such as atherosclerosis. Nuclear receptors and particularly peroxisome proliferator-activated receptors (PPARs) have emerged as therapeutic targets with a widespread impact on the treatment of metabolic disorders because they can modulate gene expression involved in lipid and glucose homeostasis and can exert anti-inflammatory properties. However, little is known about nuclear receptor effects on SMC inflammation, which produces large amounts of IL-6 and prostanoids. The aim of this study was to evaluate anti-inflammatory properties of nuclear receptor activators in a human physiological SMC model. We show that PPAR activators, as well as liver X receptor α, farnesoid X receptor and retinoid X receptor α activators, inhibit IL-1β-induced SMC 6-keto PGF1α synthesis, an index of cyclooxygenase (COX)-2 activity, with IC 50 between 1 and 69 µM. In contrast, PPARγ activators, as exemplified by rosiglitazone and pioglitazone, were unable to inhibit cytokine-induced 6-keto PGF1α synthesis. We also demonstrate for the first time that the COX-2 inhibitor rofecoxib can reduce 6-keto PGF1α production by both enzymatic inhibition and transcriptional repression. These results show that some nuclear receptor activators have SMC anti-inflammatory properties due to COX-2 inhibition which could participate in their anti-atherosclerotic properties beyond lipid impacts.