Abstract
Although more than 100 lipid metabolites have been identified, their bioactivities remain unknown. In a previous study, we discovered that the production of several lipid metabolites in the intestines dramatically changed in colitis. Of these metabolites, 5,6-dihydroxyeicosatetraenoic acid (DiHETE) possesses novel anti-inflammatory activity in the vasculature. In this study, we used mouse and human umbilical vein endothelial cell (HUVEC) models to elucidate the mechanisms underlying the vascular activity of lipid metabolites, particularly those related to the release of histamine, a major proinflammatory mediator that stimulates endothelial cells to produce NO, a mediator of vascular relaxation and hyperpermeability, by activating intracellular Ca2+ concentration-dependent signaling. In a mouse ear, the administration of 5,6-DiHETE did not induce inflammatory reactions, and pretreatment with 5,6-DiHETE inhibited histamine-induced inflammation, specifically vascular dilation and hyperpermeability. In an isolated mouse aorta, 5,6-DiHETE treatment did not influence vascular contraction but attenuated acetylcholine-induced vascular relaxation. In HUVECs, treatment with 5,6-DiHETE inhibited histamine-induced endothelial barrier disruption and inhibited the production of NO. Most notably, 5,6-DiHETE inhibited histamine-induced increases in intracellular Ca2+ concentrations in HUVECs. Our findings suggest that 5,6-DiHETE attenuates vascular hyperpermeability during inflammation by inhibiting endothelial Ca2+ elevation, which might lead to a novel pharmacological strategy against inflammatory diseases.