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

TitleActivation of mitogen-activated protein kinases by lysophosphatidylcholine-induced mitochondrial reactive oxygen species generation in endothelial cells.
Publication TypeJournal Article
Year of Publication2006
AuthorsWatanabe, N, Zmijewski, JW, Takabe, W, Umezu-Goto, M, Le Goffe, C, Sekine, A, Landar, A, Watanabe, A, Aoki, J, Arai, H, Kodama, T, Murphy, MP, Kalyanaraman, R, Darley-Usmar, VM, Noguchi, N
JournalAm J Pathol
Volume168
Issue5
Pagination1737-48
Date Published2006 May
ISSN0002-9440
KeywordsCalcium, Cell Line, Endothelial Cells, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, Humans, Lysophosphatidylcholines, MAP Kinase Kinase 4, Mitochondria, Mitogen-Activated Protein Kinases, Models, Biological, Phosphorylation, Reactive Oxygen Species, Signal Transduction, Umbilical Cord, Vitamin E
Abstract

Lysophosphatidylcholine (lysoPC) evokes diverse biological responses in vascular cells including Ca(2+) 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 Ca(2+) 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 Ca(2+) in the redox cell signaling path-ways, leading to ERK activation and adaptation of the pathological stress mediated by oxidized lipids such as lysoPC.

DOI10.2353/ajpath.2006.050648
Alternate JournalAm. J. Pathol.
Citation Key10.2353/ajpath.2006.050648
PubMed ID16651638
PubMed Central IDPMC1606607
Grant ListR01 HL058031 / HL / NHLBI NIH HHS / United States
HL58031 / HL / NHLBI NIH HHS / United States
ES10167 / ES / NIEHS NIH HHS / United States
MC_U105663142 / / Medical Research Council / United Kingdom
R01 ES010167 / ES / NIEHS NIH HHS / United States