Role of phospholipase A_2 in the cellular responses contributing to atherogenesis

氧化低密度脂蛋白（oxLDL）在动脉粥样硬化的进展中表现出许多细胞反应。在这些反应中，巨噬细胞来源的泡沫细胞的形成与巨噬细胞摄取oxLDL导致的胆固醇酯（CE）过量产生有关。CE的生产是由酰基辅酶a催化的：胆固醇酰基转移酶，它利用游离胆固醇和酰基辅酶a作为底物。然而，影响酰基辅酶a前体游离脂肪酸供应的途径尚不清楚。本研究探讨了磷脂酶A_2 （PLA_2）催化甘油磷脂水解释放游离脂肪酸可能参与CE的产生。oxLDL还诱导系膜细胞中纤维连接蛋白的产生，这是细胞外基质蛋白的一种成分，参与糖尿病肾病伴肾小球硬化的进展。本研究还探讨了PLA…More _2参与纤维连接蛋白生成的可能性。在受oxldl刺激的小鼠巨噬细胞中，CE的产生被IVA组、IVC组和VIA PLA_2组的一种抑制剂（MAFP）所抑制，而VIA PLA_2组的一种特异性抑制剂（BEL）则不受其抑制，这表明IVA组和/或IVC pla2s组的作用。即使在IVA pla_2敲低的巨噬细胞中也观察到CE的产生。然而，在IVC过表达pla_2的细胞中，oxldl诱导的CE的产生增强。在人系膜细胞中，MAFP也能抑制oxLDL诱导的纤维连接蛋白的产生，而BEL则不能。此外，在IVA PLA_2-null组小鼠系膜细胞中，oxLDL诱导的纤维连接蛋白的产生被显著阻止。这些观察结果表明，IVA和IVC PLA_2s组分别参与oxldl诱导巨噬细胞CE和系膜细胞纤维连接蛋白的产生，这与动脉粥样硬化和肾小球硬化的进展有关，是高脂血症依赖性疾病的治疗靶点之一。少

Oxidized low-density lipoprotein (oxLDL) exhibits numerous cellular responses involved in the progression of atherosclerosis. Among the responses, the formation of macrophage-derived foam cells occurs in association with the overproduction of cholesteryl ester (CE) resulting from the uptake of oxLDL by macrophages. The production of CE is catalyzed by acyl-CoA:cholesterol acyltransferase, which utilizes free cholesterol and acyl-CoA as substrates. However, the pathway contributing to the supply of free fatty acids, precursors for acyl-CoA is unclear. The present study examined the possible involvement of phospholipase A_2 (PLA_2), which catalyzes the hydrolysis of glycerophospholipids to release free fatty acids, in the production of CE. oxLDL also induces the production of fibronectin, a component of extracellular matrix proteins, in mesangial cells, being involved in the progression of diabetic nephropathy with glomerulosclerosis. In the present study, the possible involvement of PLA … More _2 in the production of fibronectin was also examined.In oxLDL-stimulated mouse macrophages, the production of CE was inhibited by an inhibitor (MAFP) of group IVA, IVC, and VIA PLA_2 isoforms, but not by a specific inhibitor (BEL) of group VIA PLA_2, suggesting the contribution of group IVA and/or IVC PLA_2s. The production of CE was also observed even in group IVA PLA_2-knockdown macrophages. However, the oxLDL-induced production of CE was enhanced in group IVC PLA_2-overexpressing cells. In human mesangial cells, oxLDL-induced production of fibronectin was also suppressed by MAFP, but not by BEL. Furthermore, in mesangial cells derived from of group IVA PLA_2-null mouse, the production of fibronectin induced by oxLDL was significantly prevented.These observations suggest that group IVA and IVC PLA_2s are involved in the oxldl-induced production of CE in macrophages and of fibronectin in mesangial cells, respectively, which are implicated in the progression of atherosclerosis and glomerulosclerosis, being one of therapeutic targets in hyperlipidemia-dependent diseases. Less