Mitogen-activated protein kinases regulate HO-1 gene transcription after ischemia-reperfusion lung injury.
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.
Zhang
Xuchen
X
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Bedard
Eric L
EL
Potter
Richard
R
Zhong
Robert
R
Alam
Jawed
J
Choi
Augustine M K
AM
Lee
Patty J
PJ
D000818:Animals; D001011:Aorta / Q000166:cytology; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006419:Heme Oxygenase (Decyclizing) / Q000032:analysis / Q000235:genetics*; D051547:Heme Oxygenase-1; D007093:Imidazoles / Q000494:pharmacology; D008171:Lung Diseases / Q000378:metabolism* / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology; D016296:Mutagenesis / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D011651:Pulmonary Artery / Q000166:cytology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D014158:Transcription, Genetic / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D008565:Membrane Proteins; D011725:Pyridines; D012333:RNA, Messenger; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one