Activation of mitogen-activated protein kinases by lysophosphatidylcholine-induced mitochondrial reactive oxygen species generation in endothelial cells.
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.
Watanabe
Nobuo
N
Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba, Meguro, Tokyo 153-8904.
Zmijewski
Jaroslaw W
JW
Takabe
Wakako
W
Umezu-Goto
Makiko
M
Le Goffe
Claire
C
Sekine
Azusa
A
Landar
Aimee
A
Watanabe
Akira
A
Aoki
Junken
J
Arai
Hiroyuki
H
Kodama
Tatsuhiko
T
Murphy
Michael P
MP
Kalyanaraman
Raman
R
Darley-Usmar
Victor M
VM
Noguchi
Noriko
N
D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008244:Lysophosphatidylcholines / Q000493:pharmacokinetics*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases; D008954:Models, Biological; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D014470:Umbilical Cord / Q000098:blood supply / Q000166:cytology; D014810:Vitamin E / Q000502:physiology
D008244:Lysophosphatidylcholines; D017382:Reactive Oxygen Species; D014810:Vitamin E; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D002118:Calcium