Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 168, Issue 5, Pages 1737-1748Publisher
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2006.050648
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Funding
- Medical Research Council [MC_U105663142] Funding Source: researchfish
- MRC [MC_U105663142] Funding Source: UKRI
- Medical Research Council [MC_U105663142] Funding Source: Medline
- NHLBI NIH HHS [R01 HL058031, HL58031] Funding Source: Medline
- NIEHS NIH HHS [R01 ES010167, ES10167] Funding Source: Medline
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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 peroxidadon 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 pathways, leading to ERK activation and adaptation of the pathological stress mediated by oxidized lipids such as lysoPC.
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