Ceramide enhances COX-2 expression and VSMC contractile hyperreactivity via ER stress signal activation.

UNLABELLED: Ceramide accumulation in blood vessels has been attributed to vascular dysfunction in progressive vascular complications in metabolic diseases. The present study showed that ceramide pretreatment promoted PE-induced vasoconstriction in rat endothelium-denuded vascular rings in a time- and dose-dependent manner. Endoplasmic reticulum (ER) stress inhibitors, 4-PBA and TUDCA, COX-2 inhibitors, Celecoxib and NS398, as well as PGE2 receptor antagonist AH-6809 attenuated ceramide-promoted vascular hyperreactivity. Ceramide promoted the transcriptional and translational expression of COX-2 and BiP in VSMCs, which were blocked by the ER stress inhibitors, 4-PBA and TUDCA. These findings show that ceramide enhances PE-induced vascular smooth muscle constriction by mediation of the ER stress/COX-2/PGE2 pathway. Therapeutic strategies targeted to reducing ER stress and COX-2 activation might be beneficial in attenuating vascular complications.

CHEMICAL COMPOUNDS: C2-Ceramide (N-acetyl-d-erythro-sphingosine) CID:2662 Tauroursodeoxycholic Acid Sodium (TUDCA) CID:9848818 phenylephrine (PE) CID:6041.