Inherited human cPLA2α deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction
Inherited human cPLA2α deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction
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DOI：
10.1172/jci30473
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发表时间：
2008-06-01
影响因子：
15.9
通讯作者：
Oates, John A.
中科院分区：
文献类型：
--
作者：
Adler, David H.;Cogan, Joy D.;Oates, John A.
胞质磷脂酶A（2 α）（cPLA（2 α））从细胞膜磷脂中水解花生四烯酸，从而为类花生酸的合成提供酶促底物，如洋地黄素和白三烯。对cPLA（2 α）功能的相当多的了解来自于对该酶的研究和cPLA（2 α）-null小鼠，但对该酶在人体中的离散作用的了解有限。我们调查了一位假设患有遗传性前列腺素类生物合成缺陷的患者，尽管没有使用环氧合酶抑制剂，但他仍患有多发性复杂性小肠溃疡。血小板产生的血栓素B-2和12-羟基二十碳四烯酸以及钙离子载体活化血液释放的白三烯B-4的水平显著降低，表明花生四烯酸底物对相应的环氧合酶和脂氧合酶的酶促释放有缺陷。二磷酸腺苷或胶原诱导的血小板聚集和脱颗粒减少，但对花生四烯酸的反应正常。在患者的cPLA（2 α）基因的编码区中发现了两个杂合单碱基对突变和一个已知的SNP（p. [Ser111Pro]+[Arg485His; Lys651Arg]）。超声处理后血小板中PLA（2）的总活性降低，前列环素、前列腺素E-2、前列腺素D-2和血栓素A（2）的尿代谢产物也减少。这些发现表征了我们认为是cPLA的一种新的遗传缺陷（2）。
Cytosolic phospholipase A(2 alpha) (cPLA(2 alpha)) hydrolyzes arachidonic acid from cellular membrane phospholipids, thereby providing enzymatic substrates for the synthesis of eicosanoids, such as prostaglandins and leukotrienes. Considerable understanding of cPLA(2 alpha) function has been derived from investigations of the enzyme and from cPLA(2 alpha)-null mice, but knowledge of discrete roles for this enzyme in humans is limited. We investigated a patient hypothesized to have an inherited prostanoid biosynthesis deficiency due to his multiple, complicated small intestinal ulcers despite no use of cyclooxygenase inhibitors. Levels of thromboxane B-2 and 12-hydroxyeicosatetraenoic acid produced by platelets and leukotriene B-4 released from calcium ionophore-activated blood were markedly reduced, indicating defective enzymatic release of the arachidonic acid substrate for the corresponding cyclooxygenase and lipoxygenases. Platelet aggregation and degranulation induced by adenosine diphosphate or collagen were diminished but were normal in response to arachidonic acid. Two heterozygous single base pair mutations and a known SNP were found in the coding regions of the patient's cPLA(2 alpha) genes (p.[Ser111Pro]+[Arg485His; Lys651Arg]). The total PLA(2) activity in sonicated platelets was diminished, and the urinary metabolites of prostacyclin, prostaglandin E-2, prostaglandin D-2, and thromboxane A(2) were also reduced. These findings characterize what we believe is a novel inherited deficiency of cPLA(2).