H(2)O(2) signals 5-HT-induced ERK MAP kinase activation and mitogenesis of smooth muscle cells.
Our previous studies have shown that 5-hydroxytryptamine (5-HT) induces cellular hyperplasia/hypertrophy through protein tyrosine phosphorylation, rapid formation of superoxide (O(2)(-)), and extracellular signal-regulated kinase (ERK)1/ERK2 mitogen-activated protein (MAP) kinase activation. Intracellularly released O(2)(-) is rapidly dismuted by superoxide dismutase (SOD) to H(2)O(2), another possible cellular growth mediator. In the present study, we assessed whether H(2)O(2) 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(2)(-) release. Thus quenching of O(2)(-) may be their mechanism for inhibition of cellular growth unrelated to p38 MAP kinase inhibition. These data indicate that generation of O(2)(-) in BPASMCs in response to 5-HT is followed by an increase in intracellular H(2)O(2) that mediates 5-HT-induced mitogenesis through activation of ERK1/ERK2 but not of p38 MAP kinase.
Lee
S L
SL
Pulmonary and Critical Care Division/Tupper Research Institute, Department of Medicine, New England Medical Center/Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Simon
A R
AR
Wang
W W
WW
Fanburg
B L
BL
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D006861:Hydrogen Peroxide / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D008938:Mitosis / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000201:enzymology*; D012701:Serotonin / Q000502:physiology*; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D002614:Chelating Agents; D012701:Serotonin; D003300:Copper; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases