Hypoxia-inducible factor-1alpha accumulation in the brain after experimental intracerebral hemorrhage.
Hypoxia-inducible factor-1 (HIF-1), a transcription factor composed of HIF-1alpha and HIF-1beta protein subunits, has been implicated in cellular protection and cell death in cerebral ischemia. The extent to which HIF-1 plays a role in brain pathology during intracerebral hemorrhage (ICH) is unknown. This study determined whether HIF-1alpha is upregulated at different time points in a rat model of ICH and the role of thrombin and red blood cell lysis in upregulation. Recently, thrombin has been implicated as a nonhypoxic regulator of HIF-1alpha in cultured smooth-muscle cells. Male Sprague-Dawley rats received intracerebral infusions of saline, autologous whole blood, blood plus hirudin, thrombin, thrombin plus hirudin, or lysed erythrocytes. Rats were killed at different time points for Western blot analysis, immunohistochemistry, immunofluorescent double staining, and reverse transcription polymerase chain reaction measurements of HIF-1alpha. HIF-1alpha protein levels increased without changing HIF-1alpha messenger RNA levels after intracerebral infusions of blood, thrombin, and lysed erythrocytes. HIF-1alpha positive cells, which proved to be neurons, were found in the brain after ICH. Hirudin, a specific thrombin inhibitor, reduced HIF-1alpha upregulation in response to both thrombin and blood. This study demonstrates that perihematomal HIF-1alpha protein is upregulated after ICH. This phenomenon is an early response of brain parenchyma to the clot. Thrombin and erythrocyte lysate are involved in HIF-1alpha upregulation through reducing HIF-1alpha degradation.
Jiang
Yajun
Y
Departments of Neurosurgery and Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Wu
Jimin
J
Keep
Richard F
RF
Hua
Ya
Y
Hoff
Julian T
JT
Xi
Guohua
G
D000818:Animals; D002543:Cerebral Hemorrhage / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006461:Hemolysis; D006490:Hemostatics / Q000494:pharmacology; D002534:Hypoxia, Brain / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008297:Male; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000494:pharmacology; D014157:Transcription Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D004268:DNA-Binding Proteins; D006490:Hemostatics; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D013917:Thrombin