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Am J Physiol Lung Cell Mol Physiol 281: L646-L652, 2001;
1040-0605/01 $5.00
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Vol. 281, Issue 3, L646-L652, September 2001

H2O2 signals 5-HT-induced ERK MAP kinase activation and mitogenesis of smooth muscle cells

S. L. Lee, A. R. Simon, W. W. Wang, and B. L. Fanburg

Pulmonary and Critical Care Division/Tupper Research Institute, Department of Medicine, New England Medical Center/Tufts University School of Medicine, Boston, Massachusetts 02111

Our previous studies have shown that 5-hydroxytryptamine (5-HT) induces cellular hyperplasia/hypertrophy through protein tyrosine phosphorylation, rapid formation of superoxide (O<UP><SUB>2</SUB><SUP>−</SUP></UP>), and extracellular signal-regulated kinase (ERK)1/ERK2 mitogen-activated protein (MAP) kinase activation. Intracellularly released O<UP><SUB>2</SUB><SUP>−</SUP></UP> is rapidly dismuted by superoxide dismutase (SOD) to H2O2, another possible cellular growth mediator. In the present study, we assessed whether H2O2 participates in 5-HT-induced mitogenic signaling. Inactivation of cellular Cu/Zn SOD by copper-chelating agents inhibited 5-HT-induced DNA synthesis of bovine pulmonary artery smooth muscle cells (BPASMCs). Infection of BPASMCs with an adenovirus containing catalase inhibited both ERK1/ERK2 MAP kinase activation and DNA synthesis induced by 5-HT. Although we could not find evidence of p38 MAP kinase activation by 5-HT, SB-203580 and SB-202190, reported inhibitors of p38 MAP kinase, inhibited the 5-HT-induced growth of BPASMCs. However, these inhibitors also inhibited 5-HT-induced O<UP><SUB>2</SUB><SUP>−</SUP></UP> release. Thus quenching of O<UP><SUB>2</SUB><SUP>−</SUP></UP> may be their mechanism for inhibition of cellular growth unrelated to p38 MAP kinase inhibition. These data indicate that generation of O<UP><SUB>2</SUB><SUP>−</SUP></UP> in BPASMCs in response to 5-HT is followed by an increase in intracellular H2O2 that mediates 5-HT-induced mitogenesis through activation of ERK1/ERK2 but not of p38 MAP kinase.

5-hydroxytryptamine; serotonin; reactive oxygen species; extracellular signal-regulated kinase; mitogen-activated protein kinase; mitogenesis


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