Activation of mitogen-activated protein kinases by lysophosphatidylcholine- induced mitochondrial reactive oxygen species generation in endothelial cells

Nobuo Watanabe, Jaroslaw W. Zmijewski, Wakako Takabe, Makiko Umezu-Goto, Claire Le Goffe, Azusa Sekine, Aimee Landar, Akira Watanabe, Junken Aoki, Hiroyuki Arai, Tatsuhiko Kodama, Michael P. Murphy, Raman Kalyanaraman, Victor M. Darley-Usmar, Noriko Noguchi

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80 Citations (Scopus)

Abstract

Lysophosphatidylcholine (lysoPC) evokes diverse biological responses in vascular cells including Ca2+ mobilization, production of reactive oxygen species, and activation of the mitogen-activated protein kinases, but the mechanisms linking these events remain unclear. Here, we provide evidence that the response of mitochondria to the lysoPC-dependent increase in cytosolic Ca2+ leads to activation of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase through a redox signaling mechanism, in human umbilical vein endothelial cells. ERK activation was attenuated by inhibitors of the electron transport chain proton pumps (rotenone and antimycin A) and an uncoupler (carbonyl cyanide p-trifluoromethoxyphenylhydrazone), suggesting that mitochondrial inner membrane potential plays a key role in the signaling pathway. ERK activation was also selectively attenuated by chain-breaking antioxidants and by vitamin E targeted to mitochondria, suggesting that transduction of the mitochondrial hydrogen peroxide signal is mediated by a lipid peroxidation product. Inhibition of ERK activation with MEK inhibitors (PD98059 or U0126) diminished induction of the antioxidant enzyme heme oxygenase-1. Taken together, these data suggest a role for mitochondrially generated reactive oxygen species and Ca2+ to the redox cell signaling pathways, leading to ERK activation and adaptation of the pathological stress mediated by oxidized lipids such as lysoPC.

Original languageEnglish
Pages (from-to)1737-1748
Number of pages12
JournalAmerican Journal of Pathology
Volume168
Issue number5
DOIs
Publication statusPublished - 2006 May
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Watanabe, N., Zmijewski, J. W., Takabe, W., Umezu-Goto, M., Le Goffe, C., Sekine, A., Landar, A., Watanabe, A., Aoki, J., Arai, H., Kodama, T., Murphy, M. P., Kalyanaraman, R., Darley-Usmar, V. M., & Noguchi, N. (2006). Activation of mitogen-activated protein kinases by lysophosphatidylcholine- induced mitochondrial reactive oxygen species generation in endothelial cells. American Journal of Pathology, 168(5), 1737-1748. https://doi.org/10.2353/ajpath.2006.050648