Hypoxia-inducible factor-1α accumulation in the brain after experimental intracerebral hemorrhage

Abstract

Hypoxia-inducible factor-1 (HIF-1), a transcription factor composed of HIF-1α 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-1α 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-1α 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-1α. HIF-1α protein levels increased without changing HIF-1α messenger RNA levels after intracerebral infusions of blood, thrombin, and lysed erythrocytes. HIF-1α positive cells, which proved to be neurons, were found in the brain after ICH. Hirudin, a specific thrombin inhibitor, reduced HIF-1α upregulation in response to both thrombin and blood. This study demonstrates that perihematomal HIF-1α 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-1α upregulation through reducing HIF-1α degradation.