Involvement of the epidermal growth factor receptor in Pb²+-induced activation of cPLA₂/COX-2 genes and PGE₂ production in vascular smooth muscle cells.
Lead (Pb²+) is one of the most common heavy metal pollutants, which can cause chronic cardiovascular diseases. To clarify the mechanism by which Pb²+ induces inflammatory reactions, we examined the expression of inflammatory genes including encoding cyclooxygenase-2 (COX-2), cytosolic phospholipase A₂ (cPLA₂), and their down stream product prostaglandin E₂ (PGE₂) in CRL1999 cells that is a vascular smooth muscle cell line from human aorta. The expression of COX-2/cPLA₂ genes and PGE₂ secretion was increased markedly after cells were exposed to 1 μM Pb²+. PD098059, a MEK inhibitor, suppressed Pb²+-mediated inflammatory reactions; this indicates the involvement of the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). Furthermore, Pb²+-induced activation of the COX-2/cPLA₂ genes was inhibited by both epidermal growth factor receptor (EGFR) inhibitors (AG1478 and PD153035) and EGFR siRNA. Short-term stimulation with Pb²+ induced EGFR phosphorylation at the Tyr residue (position, 1173). Importantly, overexpression of EGFR resulted in a significant potentiation effect on Pb²+-induced gene expression. Taken together, our results indicate that 1 μM Pb²+ can induce PGE₂ secretion by upregulating the transcription of COX-2/cPLA₂ genes. EGFR is the key target in the plasma membrane responsible for transmitting Pb²+ signals in order to trigger downstream inflammatory cascades.
Chang
Wei-Chiao
WC
Department of Medical Genetics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Chang
Chen-Chia
CC
Wang
Yung-Song
YS
Wang
Yu-Shiuan
YS
Weng
Wei-Teng
WT
Yoshioka
Tohru
T
Juo
Suh-Hang Hank
SH
D001011:Aorta / Q000166:cytology / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis*; D066246:ErbB Receptors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007854:Lead / Q000633:toxicity*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009566:Nitrates / Q000633:toxicity*; D054510:Phospholipases A2, Cytosolic / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects
D005419:Flavonoids; D009566:Nitrates; D007854:Lead; C017461:lead nitrate; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054510:Phospholipases A2, Cytosolic; D015232:Dinoprostone; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one