Group IVA phospholipase A2-mediated production of fibronectin by oxidized LDL in mesangial cells

Abstract

The deposition of atherogenic lipoproteins such as oxidized low-density lipoprotein (oxLDL) within the mesangium is involved in the overproduction of extracellular matrix proteins, a key event in the progression of glomerular diseases including glomerulosclerosis. To clarify the mechanisms underlying the oxLDL-induced production of extracellular matrix proteins, we examined the possible involvement of group IVA phospholipase A(2) (PLA(2)) using human mesangial cells and group IVA PLA(2)-deficient mouse mesangial cells. oxLDL accelerated the production of fibronectin and collagen (type IV), components of extracellular matrix proteins, with the preceding release of arachidonic acid. Methyl arachidonyl fluorophosphonate (MAFP), known as an inhibitor of group IVA PLA(2), markedly suppressed the oxLDL-induced production of fibronectin as well as the release of arachidonic acid, whereas it did not inhibit the production of collagen. The inhibitory effect of MAFP on the production of fibronectin was reversed by adding arachidonic acid and 12-hydroxyeicosatetraenoic acid. Furthermore, we found that in group IVA PLA(2)-deficient mouse mesangial cells, the production of fibronectin in response to oxLDL was weak as compared with that in wild-type cells. However, the production by oxLDL of collagen was not suppressed in the group IVA PLA(2)-deficient cells. These findings suggest that group IVA PLA(2) is involved in the production of fibronectin in oxLDL-stimulated mesangial cells.