Hepatocyte growth factor protects against hypoxia/reoxygenation-induced apoptosis in endothelial cells.
Hypoxia/reoxygenation causes cellular injury and death associated with a number of pathophysiological conditions, including myocardial ischemia/reperfusion injury and stroke. The cell death pathways induced by hypoxia/reoxygenation and their underlying regulatory mechanisms remain poorly understood. Recent studies have shown that hypoxia/reoxygenation can induce Bax translocation and cytochrome c release. Using murine lung endothelial cells as a model, we found that the induction of apoptosis by hypoxia/reoxygenation involved the activation of both Bax-dependent and death receptor-mediated pathways. We demonstrated the activation of the death-inducing signal complex and Bid pathway after hypoxia/reoxygenation. Hepatocyte growth factor markedly inhibited hypoxia/reoxygenation-induced endothelial cell apoptosis. The cytoprotection afforded by hepatocyte growth factor was mediated in part by the stimulation of FLICE-like inhibiting protein expression, the attenuation of death-inducing signal complex formation, and the inhibition of Bid and Bax activation. Hepatocyte growth factor also prevented cell injury and death by increasing the expression of the antiapoptotic Bcl-XL protein. The inhibition of Bid/Bax-induced cell death by hepatocyte growth factor primarily involved p38 MAPK and in part Akt-dependent pathways but not ERK1/ERK2.
Wang
Xue
X
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA.
Zhou
Yushen
Y
Kim
Hong Pyo
HP
Song
Ruiping
R
Zarnegar
Reza
R
Ryter
Stefan W
SW
Choi
Augustine M K
AM
D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D015536:Down-Regulation; D042783:Endothelial Cells / Q000166:cytology* / Q000473:pathology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D000860:Hypoxia; D008168:Lung / Q000166:cytology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D048051:p38 Mitogen-Activated Protein Kinases
D051023:BH3 Interacting Domain Death Agonist Protein; C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; C494815:Bid protein, mouse; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D017228:Hepatocyte Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases; D010100:Oxygen