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Dynamic changes of the anti- and pro-apoptotic proteins Bcl-w, Bcl-2, and Bax with Smac/Diablo mitochondrial release after photothrombotic ring stroke in rats
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå Stroke Centre, Umeå University Hospita.
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2004 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 20, no 5, p. 1177-1188Article in journal (Refereed) Published
Abstract [en]

The anti‐apoptotic proteins Bcl‐w and Bcl‐2 and the pro‐apoptotic protein Bax may mediate cell death or survival via regulation of the mitochondria including second mitochondria‐derived activator of caspase (Smac)/direct inhibitor of apoptosis protein (IAP)‐binding protein with low pI (DIABLO) release. This study aimed to explore alterations in Bcl‐w, Bcl‐2, and Bax and the relationship between these proteins and Smac/DIABLO by means of in situ hybridization, immunohistochemical (IHC) staining, and Western blots after low‐ and high‐intensity photothrombotic ring stroke. At 4 h after low‐intensity irradiation, we found widespread bcl‐w overexpression on both the mRNA and protein levels in the bilateral cortex except the ring lesion region and in subcortical regions. A prolonged elevation of Bcl‐2 with relatively unchanged Bax in the mitochondrial fraction was demonstrated from 4 to 72 h. These upregulated anti‐apoptotic proteins combined with little Smac/DIABLO release might be associated with increased cell survival and thereby remarkable morphological recovery after low‐intensity irradiation. After high‐intensity irradiation, we observed decreased bcl‐w and bcl‐2 mRNA with increased Bcl‐2 protein in the cytosolic fraction, whereas the Bax protein remained in scattered ischaemic cells in the ring lesion and the region at risk that corresponded with release of Smac/DIABLO from mitochondria to the cytosol at 1–24 h. These changes might be related to the massive cell death observed after high‐intensity irradiation. Taken together, the balance and the location of anti‐apoptotic proteins vs. pro‐apoptotic proteins could be associated with the translocation of Smac/DIABLO from the mitochondria to the cytosol and therefore closely related to cell death or survival after focal cerebral ischaemia.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2004. Vol. 20, no 5, p. 1177-1188
Keywords [en]
Animals, Apoptosis/*physiology, Apoptosis Regulatory Proteins, Brain/metabolism, Carrier Proteins/analysis/*biosynthesis, Cell Survival/physiology, Cerebrovascular Accident/*metabolism, Intracranial Thrombosis/metabolism, Mitochondrial Proteins/analysis/*biosynthesis, Protein Biosynthesis, Proteins/analysis, Proto-Oncogene Proteins c-bcl-2/analysis/*biosynthesis, RNA; Messenger/analysis/biosynthesis, Rats, bcl-2-Associated X Protein
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-12979DOI: 10.1111/j.1460-9568.2004.03554.xISI: 000224041300004PubMedID: 15341589OAI: oai:DiVA.org:umu-12979DiVA, id: diva2:152650
Available from: 2007-09-13 Created: 2007-09-13 Last updated: 2019-03-19Bibliographically approved
In thesis
1. Apoptotic and necrotic cell death after photothrombotic ring stroke: characterization of a stroke model and its morphological and molecular consequences
Open this publication in new window or tab >>Apoptotic and necrotic cell death after photothrombotic ring stroke: characterization of a stroke model and its morphological and molecular consequences
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cerebral ischemic cell death is a major cause of disability and death among stroke patients. The brain cell demise can occur through apoptosis or necrosis or as a continuum of both. This study aimed at establishing a dual setup of a photothrombotic ring stroke model and exploring its morphological and molecular consequences.

    Photothrombotic ring stroke was induced in adult male Wistar rats by a ring shaped laser irradiation beam (514.5nm, outer diameter 5mm, thickness 0.35 mm) for 120 seconds focused on the exposed intact skull bone with simultaneous intravenous infusion of the photosensitizer erythrosin B (17 mg/kg). By using otherwise identical experimental conditions, high intensity irradiation (1.94 W/cm2) resulted in consistent lack of reperfusion in the region at risk whereas low intensity irradiation (0.90 W/cm2) induced late spontaneous reperfusion. The morphological appearance of apoptotic and necrotic cells was demonstrated by H&E, TUNEL and Hoechst stainings under light microscopy, immunohistochemistry and electron microscopy. This was further confirmed by gel electrophoresis showing DNA laddering that coexisted with DNA smear. Cell counts revealed that apoptotic cells appeared earlier (at 24 h) and remained as long as the necrotic cells, that is up to 72 hours after ischemic onset in regions with severe CBF reduction. After low intensity irradiation, we observed early and widespread increased expression of the anti-apoptotic protein bcl-w and a prolonged elevation of Bcl-2 with unchanged pro-apoptotic Bax in mitochondria. In contrast, decreased bcl-w and Bcl-2 with scattered Bax remained after high intensity irradiation. Correspondingly, the release of the pro-apoptotic factor Smac/DIABLO from the mitochondria to the cytosol was more persistent in high- compared with low-intensity irradiation.   

    Apoptotic and necrotic cell death coexisted in the same regions at the same time after photothrombotic ring stroke induced by low- or high-intensity irradiation, where spontaneous morphological recovery or pannecrosis were evident in the region at risk. The ratios between Bcl-w, Bcl-2 and Bax may direct the translocation of Smac/DIABLO from the mitochondria to the cytosol and thereby influence cell death or survival after focal cerebral ischemia.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2003. p. 59
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 826
National Category
Medical and Health Sciences Neurosciences
Identifiers
urn:nbn:se:umu:diva-133950 (URN)91-7305-390-2 (ISBN)
Public defence
2003-02-28, Sal B, plan 9, By 1D, NUS, Umeå, 13:00 (English)
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Available from: 2019-03-19 Created: 2017-04-22 Last updated: 2019-03-21Bibliographically approved

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Hu, Xiao-LeiOlsson, TommyJohansson, Inga-MajBrännström, ThomasWester, Per

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