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(American Journal of Pathology. 2006;168:1737-1748.)
© 2006 American Society for Investigative Pathology

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 and Noriko Noguchi^*,**

From the Research Center for Advanced Science and Technology,^* and Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan; Chugai Pharmaceutical Co. Ltd., Tokyo, Japan; the Center for Free Radical Biology and Department of Pathology, University of Alabama, Birmingham, Alabama; the MRC-Dunn Human Nutrition Unit,^¶ Cambridge, United Kingdom; the Medical College of Wisconsin,|| Milwaukee, Wisconsin; and the Faculty of Engineering,^** Doshisha University, Kyoto, Japan

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⁺ in the redox cell signaling path-ways, leading to ERK activation and adaptation of the pathological stress mediated by oxidized lipids such as lysoPC.

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