Cox D A, Cohen M L
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 47628, USA.
J Pharmacol Exp Ther. 1997 Oct;283(1):305-11.
Lysophosphatidylcholine (lysoPC) causes endothelial vasomotor dysfunction in isolated blood vessels, although the signaling pathways involved in this effect remain to be established. Although lysoPC stimulated phospholipase D (PLD) activity in cultured endothelial cells, the role of PLD in the vascular effects of lysoPC remains unclear. This study investigated the hypothesis that PLD is involved in lysoPC-induced endothelial vasomotor dysfunction in isolated rabbit aorta. LysoPC (3-30 microM) stimulated vascular PLD activity and inhibited endothelium-dependent vasorelaxation to acetylcholine within an identical concentration range. In contrast, lysoPC-induced inhibition of vasorelaxation was not prevented by the selective protein kinase C (PKC) inhibitor, GF109203X (3 microM), which suggested that this enzyme was not involved in the endothelial vasomotor dysfunction produced by lysoPC. The ability of two other lysophospholipids, lyso-platelet-activating factor (3-30 microM) and lysophosphatidylserine (10-30 microM) to induce endothelial vasomotor dysfunction was also associated closely with their ability to stimulate vascular PLD activity. Parallel stimulation of PLD activity and inhibition of acetylcholine-induced relaxation was also observed with orthovanadate (0.1-3 mM), which suggested that the association between PLD activation and endothelial vasomotor dysfunction was not a phenomenon particular to lysophospholipids. The magnitude of PLD stimulation and the extent of endothelial dysfunction induced by these diverse stimuli were highly correlated (r2 = 0.88). These observations suggest that the PLD signal transduction pathway is important in the endothelial vasomotor dysfunction produced by lysophospholipids and perhaps other agents.
溶血磷脂酰胆碱（lysoPC）可导致离体血管的内皮血管舒缩功能障碍，尽管参与此效应的信号通路仍有待确定。虽然lysoPC可刺激培养的内皮细胞中的磷脂酶D（PLD）活性，但PLD在lysoPC血管效应中的作用仍不清楚。本研究探讨了PLD参与lysoPC诱导的离体兔主动脉内皮血管舒缩功能障碍这一假说。LysoPC（3 - 30微摩尔）在相同浓度范围内刺激血管PLD活性并抑制对乙酰胆碱的内皮依赖性血管舒张。相反，选择性蛋白激酶C（PKC）抑制剂GF109203X（3微摩尔）并不能阻止lysoPC诱导的血管舒张抑制，这表明该酶不参与lysoPC产生的内皮血管舒缩功能障碍。另外两种溶血磷脂，溶血血小板活化因子（3 - 30微摩尔）和溶血磷脂酰丝氨酸（10 - 30微摩尔）诱导内皮血管舒缩功能障碍的能力也与其刺激血管PLD活性的能力密切相关。用原钒酸盐（0.1 - 3毫摩尔）也观察到PLD活性的平行刺激和对乙酰胆碱诱导的舒张的抑制，这表明PLD激活与内皮血管舒缩功能障碍之间的关联并非溶血磷脂所特有的现象。这些不同刺激所引起的PLD刺激程度和内皮功能障碍程度高度相关（r2 = 0.88）。这些观察结果表明，PLD信号转导通路在溶血磷脂以及可能其他因子产生的内皮血管舒缩功能障碍中起重要作用。
