19,20-EpDPE, a bioactive CYP450 metabolite of DHA monoacyglyceride, decreases Ca2+ sensitivity in human pulmonary arteries

Morin C, Fortin S, Rousseau E. 19,20-EpDPE, a bioactive CYP450 metabolite of DHA monoacyglyceride, decreases Ca2+ sensitivity in human pulmonary arteries. Am J Physiol Heart Circ Physiol 301: H1311-H1318, 2011. First published August 5, 2011; doi: 10.1152/ajpheart.00380.2011.-The aim of this study was to investigate the effect of docosahexaenoic acid monoacylglyceride (MAG-DHA) on human pulmonary arterial tone. Tension measurements on pulmonary arterial tissues demonstrated that MAG-DHA reduced U-46619-induced tone, which is highly sensitive to the H-1152 inhibitor. Results also showed that MAG-DHA treatments decreased RhoA activity levels, which in turn inactivated the Rho-kinase pathway, leading to a reduction in U-46619-induced Ca2+ sensitivity of permeabilized pulmonary artery smooth muscle cells. According to the mechanical responses assessing U-46619-induced Ca2+ sensitivity in the absence or presence of 3 mu M MAG-DHA, MAG-DHA plus 1 mu M N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH, a cytochrome P-450 epoxygenase inhibitor) and 300 nM 19,20-epoxydocosapentaenoic acid (a cytochrome P-450 epoxygenase-dependent DHA metabolite), our data suggest that the MAG-DHA is metabolized in a bioactive epoxymetabolite. This epoxyeicosanoid in turn decreases active tone and Ca2+ sensitivity of smooth muscles cells through an inhibition of the Rho-kinase pathway. Together, these data provide primary evidence regarding the mode of action of MAG-DHA in human pulmonary arteries and suggest that this compound may be of pharmacological interest in patients with pulmonary hypertension to generate intracellular bioactive metabolites.