TY - JOUR
T1 - Activation of mitogen-activated protein kinases by lysophosphatidylcholine- induced mitochondrial reactive oxygen species generation in endothelial cells
AU - Watanabe, Nobuo
AU - Zmijewski, Jaroslaw W.
AU - Takabe, Wakako
AU - Umezu-Goto, Makiko
AU - Le Goffe, Claire
AU - Sekine, Azusa
AU - Landar, Aimee
AU - Watanabe, Akira
AU - Aoki, Junken
AU - Arai, Hiroyuki
AU - Kodama, Tatsuhiko
AU - Murphy, Michael P.
AU - Kalyanaraman, Raman
AU - Darley-Usmar, Victor M.
AU - Noguchi, Noriko
PY - 2006/5
Y1 - 2006/5
N2 - 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.
AB - 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.
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U2 - 10.2353/ajpath.2006.050648
DO - 10.2353/ajpath.2006.050648
M3 - Article
C2 - 16651638
AN - SCOPUS:33646508129
VL - 168
SP - 1737
EP - 1748
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 5
ER -