Involvement of the epidermal growth factor receptor in Pb 2+-induced activation of cPLA 2/COX-2 genes and PGE 2 production in vascular smooth muscle cells

Abstract

Lead (Pb 2+) is one of the most common heavy metal pollutants, which can cause chronic cardiovascular diseases. To clarify the mechanism by which Pb 2+ induces inflammatory reactions, we examined the expression of inflammatory genes including encoding cyclooxygenase-2 (COX-2), cytosolic phospholipase A 2 (cPLA 2), and their down stream product prostaglandin E 2 (PGE 2) in CRL1999 cells that is a vascular smooth muscle cell line from human aorta. The expression of COX-2/cPLA 2 genes and PGE 2 secretion was increased markedly after cells were exposed to 1 μM Pb 2+. PD098059, a MEK inhibitor, suppressed Pb 2+-mediated inflammatory reactions; this indicates the involvement of the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). Furthermore, Pb 2+-induced activation of the COX-2/cPLA 2 genes was inhibited by both epidermal growth factor receptor (EGFR) inhibitors (AG1478 and PD153035) and EGFR siRNA. Short-term stimulation with Pb 2+ induced EGFR phosphorylation at the Tyr residue (position, 1173). Importantly, overexpression of EGFR resulted in a significant potentiation effect on Pb 2+-induced gene expression. Taken together, our results indicate that 1 μM Pb 2+ can induce PGE 2 secretion by upregulating the transcription of COX-2/cPLA 2 genes. EGFR is the key target in the plasma membrane responsible for transmitting Pb 2+ signals in order to trigger downstream inflammatory cascades.