alexa HDL3 induces cyclooxygenase-2 expression and prostacyclin release in human endothelial cells via a p38 MAPK CRE-dependent pathway: effects on COX-2 PGI-synthase coupling.
Diabetes & Endocrinology

Diabetes & Endocrinology

Journal of Diabetes & Metabolism

Author(s): Norata GD, Callegari E, Inoue H, Catapano AL

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Abstract OBJECTIVE: In endothelial cells, cyclooxygenase-1 (COX-1) and COX-2 both contribute to prostacyclin production. Recent findings suggest that COX-2 contributes significantly to systemic prostacyclin synthesis in humans; whether COX-2 inhibition is related to an increased cardiovascular risk is undergoing debate. HDLs have been shown to increase prostacyclin synthesis, thus in the present study we investigated the molecular mechanisms involved in this effect in endothelial cells. METHODS AND RESULTS: HDL3 (30 microg/mL) induced COX-2 expression in a time- and dose-dependent manner. COX-2 was found mainly in the perinuclear area where it co-localizes with PGI synthase. Transient transfection experiments showed that CRE is required for HDL-induced COX-2 transcription, and we demonstrated that p38 MAPK activation by HDL3 is involved in COX-2 mRNA transcription and stabilization. As a consequence of COX-2-induction by HDL3 prostacyclin production increased, incubation with a COX-2 selective inhibitor blocked this effect. Moreover, HDL3 increased caveolin-1 phosphorylation, thus promoting PGI-synthase shuttling from the membrane to the perinuclear area. CONCLUSIONS: We conclude that in endothelial cells, HDL modulates COX-2/PGI-S activity via both p38 MAPK-dependent COX-2 mRNA stability and transcription and both caveolin-1-dependent PGI-synthase shuttling and COX-2 coupling. The understanding of these mechanisms may provide new insights into the antiatherogenic role of HDL. This article was published in Arterioscler Thromb Vasc Biol and referenced in Journal of Diabetes & Metabolism

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