Role of phospholipase A_2 in the cellular responses contributing to atherogenesis

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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