Acyl Chain-Dependent Effect of Lysophosphatidylcholine on Endothelium-Dependent Vasorelaxation

Previously we identified palmitoyl-, oleoyl-, linoleoyl-, and arachidonoyl-lysophosphatidylcholine (LPC 16:0, 18:1, 18:2 and 20:4) as the most prominent LPC species generated by endothelial lipase (EL). In the present study, we examined the impact of those LPC on acetylcholine (ACh)- induced vascular relaxation. All tested LPC attenuated ACh-induced relaxation, measured ex vivo, using mouse aortic rings and wire myography. The rank order of potency was as follows: 18:2>20:4>16:0>18:1. The attenuating effect of LPC 16:0 on relaxation was augmented by indomethacin-mediated cyclooxygenase (COX)-inhibition and CAY10441, a prostacyclin (PGI2)- receptor (IP) antagonist. Relaxation attenuated by LPC 20:4 and 18:2 was improved by indomethacin and SQ29548, a thromboxane A2 (TXA2)- receptor antagonist. The effect of LPC 20:4 could also be improved by TXA2- and PGI2-synthase inhibitors. As determined by EIA assays, the tested LPC promoted secretion of PGI2, TXA2, PGF2α, and PGE2, however, with markedly different potencies. LPC 16:0 was the most potent inducer of superoxide anion production by mouse aortic rings, followed by LPC 18:2, 20:4 and 18:1, respectively. The strong antioxidant tempol recovered relaxation impairment caused by LPC 18:2, 18:1 and 20:4, but not by LPC 16:0. The tested LPC attenuate ACh-induced relaxation through induction of proconstricting prostanoids and superoxide anions. The potency of attenuating relaxation and the relative contribution of underlying mechanisms are strongly related to LPC acyl-chain length and degree of saturation.

此前，我们已鉴定出棕榈酰基、油酰基、亚油酰基及花生四烯酰基溶血磷脂酰胆碱（对应亚型分别为LPC 16:0、18:1、18:2与20:4）为内皮脂肪酶（endothelial lipase, EL）所生成的主要溶血磷脂酰胆碱（lysophosphatidylcholine, LPC）亚型。本研究中，我们考察了上述LPC对乙酰胆碱（acetylcholine, ACh）诱导的血管舒张的影响。本实验采用离体小鼠主动脉环与钢丝肌动描记法进行检测，结果显示所有受试LPC均会削弱ACh诱导的血管舒张效应，其作用强度排序为：18:2＞20:4＞16:0＞18:1。LPC 16:0的舒张抑制效应可被吲哚美辛介导的环氧合酶（cyclooxygenase, COX）抑制作用以及前列环素（prostacyclin, PGI2）受体（IP）拮抗剂CAY10441进一步增强。LPC 20:4与18:2所介导的血管舒张抑制效应，可经吲哚美辛与血栓烷A2（thromboxane A2, TXA2）受体拮抗剂SQ29548得到缓解。LPC 20:4的该效应还可通过TXA2与PGI2合酶抑制剂得到改善。酶免疫分析法（enzyme immunoassay, EIA）检测结果显示，受试LPC可促进PGI2、TXA2、PGF2α及PGE2的分泌，但其作用强度存在显著差异。LPC 16:0是诱导小鼠主动脉环生成超氧阴离子的最强效物质，其后依次为LPC 18:2、20:4与18:1。强效抗氧化剂Tempol可恢复LPC 18:2、18:1与20:4所导致的舒张功能损伤，但无法逆转LPC 16:0引发的该效应。受试LPC可通过诱导缩血管前列腺素类物质生成与超氧阴离子产生，削弱ACh诱导的血管舒张效应。其舒张抑制效应的强度，以及背后潜在机制的相对贡献程度，均与LPC的酰基链长度及饱和程度密切相关。