Abstract
Lung ischemia-reperfusion (I-R) is an important model of oxidant-mediated acute lung and vascular injury. Heme oxygenase-1 (HO-1) is a cytoprotective gene that is markedly induced by lung I-R injury. HO-1 mRNA is increased in mouse lung after 30 min of lung hilar clamping (ischemia) followed by 2-6 h of unclamping (reperfusion) compared with control mice. In a variety of vascular cell types, HO-1 mRNA is induced after 24 h of anoxia followed by 30 min-1 h of reoxygenation (A-R). Transfection studies reveal that the promoter and 5'-distal enhancer E1 are necessary and sufficient for increased HO-1 gene transcription after A-R. Immunoblotting studies show all three subfamilies of MAPKs (ERK, JNK, and p38) are activated by 15 min of reperfusion. We also demonstrate that HO-1 gene transcription after A-R involves ERK, JNK, and p38 MAPK pathways. Together, our data show that I-R not only induces HO-1 gene expression in mouse lungs and vascular cells but that gene transcription occurs via the promoter and E1 enhancer and involves upstream MAPK pathways.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Aorta / cytology
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Cells, Cultured
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Enhancer Elements, Genetic / physiology
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Gene Expression Regulation, Enzymologic / physiology*
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Heme Oxygenase (Decyclizing) / analysis
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Heme Oxygenase (Decyclizing) / genetics*
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Heme Oxygenase-1
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Imidazoles / pharmacology
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Lung Diseases / metabolism*
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Lung Diseases / physiopathology
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MAP Kinase Signaling System / physiology*
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Membrane Proteins
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Mice
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Mitogen-Activated Protein Kinase 9
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / enzymology
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Mutagenesis / physiology
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Promoter Regions, Genetic / physiology
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Pulmonary Artery / cytology
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Pyridines / pharmacology
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RNA, Messenger / analysis
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Rats
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Reperfusion Injury / metabolism*
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Reperfusion Injury / physiopathology
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Transcription, Genetic / physiology
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p38 Mitogen-Activated Protein Kinases
Substances
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Enzyme Inhibitors
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Flavonoids
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Imidazoles
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Membrane Proteins
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Pyridines
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RNA, Messenger
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Heme Oxygenase (Decyclizing)
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Heme Oxygenase-1
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Hmox1 protein, mouse
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Mitogen-Activated Protein Kinase 9
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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SB 203580
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one