Hydrolysis of phosphatidylserine-exposing red blood cells by secretory phospholipase A2 generates lysophosphatidic acid and results in vascular dysfunction
Hydrolysis of phosphatidylserine-exposing red blood cells by secretory phospholipase A2 generates lysophosphatidic acid and results in vascular dysfunction
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DOI：
10.1074/jbc.m505790200
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发表时间：
2006-01-13
影响因子：
4.8
通讯作者：
Kuypers, FA
中科院分区：
文献类型：
--
作者：
Neidlinger, NA;Larkin, SK;Kuypers, FA
IIa 型分泌型磷脂酶 A(2) (sPLA(2)) 在炎症中升高，分解膜磷脂并产生花生四烯酸。我们假设 sPLA(2) 会水解暴露磷脂酰丝氨酸 (PS) 的红细胞，并从暴露 PS 的红细胞中升高的磷脂酸生成溶血磷脂酸 (LPA)。反过来，LPA 作为一种强大的脂质介质，可能会影响血管内皮细胞的功能。虽然正常红细胞不受 sPLA2 的影响，但在炎症条件下观察到的 sPLA2 水平 (100 ng/ml) 暴露 PS 的红细胞溶血并产生 LPA (1.2 nM/10(8) RBC)。当内皮细胞单层在体外与 LPA 一起孵育时，注意到融合的损失。此外，在体内用5μM LPA的大鼠肠系膜小静脉中发现水力传导率呈剂量依赖性增加，并且暴露PS的红细胞与PLA(2)的组合引起类似的渗透性增加。在N-棕榈酰L-丝氨酸磷酸（内皮LPA受体的竞争性抑制剂）存在下，体外融合丧失和体内5μM LPA引起的水力渗透性被消除。本研究表明，在细胞膜磷脂不对称性丧失的情况下，炎症中 sPLA(2) 活性的增加可导致 LPA 介导的内皮功能障碍和血管完整性丧失。
Secretory phospholipase A(2) (sPLA(2)) type IIa, elevated in inflammation, breaks down membrane phospholipids and generates arachidonic acid. We hypothesized that sPLA(2) will hydrolyze red blood cells that expose phosphatidylserine ( PS) and generate lysophosphatidic acid (LPA) from phosphatidic acid that is elevated in PS-exposing red blood cells. In turn, LPA, a powerful lipid mediator, could affect vascular endothelial cell function. Although normal red blood cells were not affected by sPLA2, at levels of sPLA2 observed under inflammatory conditions (100 ng/ml) PS-exposing red blood cells hemolyzed and generated LPA (1.2 nM/10(8) RBC). When endothelial cell monolayers were incubated in vitro with LPA, a loss of confluence was noted. Moreover, a dose-dependent increase in hydraulic conductivity was identified in rat mesenteric venules in vivo with 5 mu M LPA, and the combination of PS-exposing red blood cells with PLA(2) caused a similar increase in permeability. In the presence of N-palmitoyl L-serine phosphoric acid, a competitive inhibitor for the endothelial LPA receptor, loss of confluence in vitro and the hydraulic permeability caused by 5 mu M LPA in vivo were abolished. The present study demonstrates that increased sPLA(2) activity in inflammation in the presence of cells that have lost their membrane phospholipid asymmetry can lead to LPA-mediated endothelial dysfunction and loss of vascular integrity.