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CELLULAR AND MOLECULAR

Hydrogen Peroxide-Induced Extracellular Signal-Regulated Kinase Activation in Cultured Feline Ileal Smooth Muscle Cells

Department of Pharmacology, College of Pharmacy, Chung Ang University, Seoul, Korea

H₂O₂ has been shown to act as a signaling molecule involved in many cellular functions such as apoptosis and proliferation. In the present study, we characterized the effects of H₂O₂ on the activation of mitogen-activated protein (MAP) kinases and examined the factors involved in the process of extracellular signal-regulated kinase (ERK) activation by H₂O₂ in ileal smooth muscle cells (ISMC). ISMC were cultured and exposed to H₂O₂. Western blot analysis was performed with phosphospecific MAP kinase antibodies. Potent activation of ERK and moderate activation of stress-activated protein kinase/c-Jun NH₂-terminal kinase occurred within 30 min of 1 mM H₂O₂ treatment. However, p38 MAP kinase was not activated by H₂O₂. The activation of ERK by H₂O₂ was reduced by the mitogen-activated/ERK-activating kinase inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one], Ras inhibitor S-farnesylthiosalicylic acid, removal of extracellular Ca²⁺, depletion of the intracellular Ca²⁺ pool by thapsigargin, or pretreatment of ISMC with the calmodulin antagonist W-7. Also, H₂O₂-induced ERK activation was attenuated by a receptor tyrosine kinase inhibitor, tyrphostin 51, but not by down-regulation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate or by a PKC inhibitor, GF109203X [3-[1-(dimethylaminopropyl)indol-3-yl]-4-(indol-3-yl)maleimide hydrochloride]. Growth factor receptor antagonist suramin pretreatment inhibited H₂O₂-induced ERK activation, highlighting a role for growth factor receptors in this activation. Furthermore, the ERK activation by H₂O₂ was blocked by pretreatment with either N-acetyl-cysteine, o-phenanthroline, or mannitol indicating that metal-catalyzed free radical formation may mediate the initiation of signal transduction by H₂O₂. These data suggest that short-term stimulation with H₂O₂ activates the signaling pathways of cell mitogenic effects which are thought to be a protective response against intestinal oxidative stress.

Address correspondence to: Professor Uy Dong Sohn, 221 Heuksukdong, Dongjakgu, Department of Pharmacology, College of Pharmacy, Chung Ang University, Seoul 156-756 Korea, Republic of Korea. E-mail: udsohn{at}cau.ac.kr

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