SCF Pharma, Sainte-Luce, Canada.
Am J Physiol Heart Circ Physiol. 2011 Oct;301(4):H1311-8. doi: 10.1152/ajpheart.00380.2011. Epub 2011 Aug 5.
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 Ca(2+) sensitivity of permeabilized pulmonary artery smooth muscle cells. According to the mechanical responses assessing U-46619-induced Ca(2+) sensitivity in the absence or presence of 3 μM MAG-DHA, MAG-DHA plus 1 μM 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 Ca(2+) 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.
本研究旨在探讨二十二碳六烯酸单酰甘油（MAG-DHA）对人肺动脉张力的影响。肺动脉组织张力测量表明，MAG-DHA 可降低 U-46619 诱导的张力，对 H-1152 抑制剂高度敏感。结果还表明，MAG-DHA 处理可降低 RhoA 活性水平，从而使 Rho-激酶途径失活，导致 U-46619 诱导的通透性肺动脉平滑肌细胞 Ca(2+)敏感性降低。根据评估 U-46619 诱导的 Ca(2+)敏感性的机械反应，在不存在或存在 3 μM MAG-DHA 的情况下，MAG-DHA 加 1 μM N-甲基磺酰基-6-(2-丙炔氧基苯基)己酰胺（MS-PPOH，细胞色素 P-450 环氧化物酶抑制剂）和 300 nM 19,20-环氧二十二碳五烯酸（细胞色素 P-450 环氧化物酶依赖性 DHA 代谢物），我们的数据表明，MAG-DHA 代谢为生物活性环氧代谢物。这种环氧二十碳三烯酸反过来通过抑制 Rho-激酶途径降低平滑肌细胞的活性张力和 Ca(2+)敏感性。总之，这些数据为 MAG-DHA 在人肺动脉中的作用模式提供了初步证据，并表明该化合物在肺动脉高压患者中可能具有药理学意义，可产生细胞内生物活性代谢物。
