Docosahexaenoic acid inhibits TNFα-induced ICAM-1 expression by activating PPARα and autophagy in human endothelial cells

Inflammation plays a key role in the development of cardiovascular disease (CVD), and docosahexaenoic acid (DHA) is recognized to fight against CVD. PPAR alpha belongs to the nuclear hormone receptor superfamily and can interfere with inflammatory processes. Autophagy can degrade inflammasome proteins and counteract inflammation. Overexpression of intercellular adhesion molecule (ICAM) 1 in endothelial cells contributes to monocyte migration into the vascular intima. Here we investigated the mechanisms by which DHA inhibits TNF alpha-induced ICAM-1 expression in EA. hy926 endothelial cells. DHA markedly activated PPAR alpha and suppressed TNF alpha-induced ICAM-1 expression, ICAM-1 promoter activity, p65 nuclear translocation, NF kappa B and DNA binding activity, and THP-1 cell adhesion. PPAR alpha knockdown abolished the ability of DHA to inhibit TNF alpha-induced ICAM-1 expression and THP-1 cell adhesion. The PPAR alpha antagonist GW6471 reversed the inhibitory effect of DHA on TNF alpha-induced ICAM-1 expression, p65 nuclear translocation, NF kappa B and DNA binding activity, and THP-1 cell adhesion. DHA significantly activated autophagy as evidenced by the formation of autophagosomes and increased LC3II protein expression. By contrast, wortmannin, which inhibits autophagy, abrogated DHA-induced autophagy and the inhibition of TNF alpha-induced ICAM-1 protein expression by DHA. Our results suggest that DHA likely inhibits TNF alpha-induced ICAM-1 expression by activating PPAR alpha and autophagy.