Document Detail


Cardiomyocyte-targeted HIF-1alpha gene therapy inhibits cardiomyocyte apoptosis and cardiac allograft vasculopathy in the rat.
MedLine Citation:
PMID:  20580263     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Hypoxia-inducible factor-1 (HIF-1), a key transcription factor in hypoxia, affects a wide range of adaptive cell functions. We examined the kinetics of endogenous HIF-1alpha during acute and chronic rejection, and the effect of exogenous HIF-1alpha in chronically rejecting rat cardiac allografts.
METHODS: Heterotopic cardiac transplantations were performed between major MHC-mismatched Dark Agouti and Wistar-Furth rats. Cyclosporine A (CsA) was used to prevent acute rejection in the chronic rejection model. The effect of HIF-1alpha overexpression was investigated by adeno-assocated virus 2 (AAV2)-mediated gene transfer of a constitutively stabilized form of mouse HIF-1alpha (AAV-HIF-1alpha). The analysis of allografts was based on histology, immunohistochemistry and quantitative reverse transcript-polymerase chain reaction (RT-PCR).
RESULTS: Acute and chronic rejection significantly induced HIF-1alpha mRNA in rat cardiac allografts when compared with syngeneic controls. Immunohistochemistry localized significantly increased HIF-1alpha immunoreactivity to vascular smooth muscle cells, vascular endothelial cells, post-capillary venules and graft-infiltrating mononuclear inflammatory cells of the allograft, whereas expression in cardiomyocytes remained unchanged. Regression analysis revealed a linear correlation between the progression of cardiac allograft vasculopathy (CAV) and HIF-1alpha immunoreactivity in post-capillary venules and graft-infiltrating mononuclear inflammatory cells in chronically rejecting rat cardiac allografts. AAV-HIF-1alpha enhanced cardiomyocyte HIF-1alpha production and significantly reduced cardiomyocyte apoptosis and the development of CAV in chronically rejecting rat cardiac allografts.
CONCLUSIONS: We found that acute and chronic rejection increased HIF-1alpha mRNA and protein levels in rat cardiac allografts. On the other hand, cardiomyocyte-targeted HIF-1alpha gene transfer inhibited cardiomyocyte apoptosis and the development of CAV, suggesting a novel therapeutic strategy for HIF-1alpha in cardiac allografts.
Authors:
Mikko A I Keränen; Antti I Nykänen; Rainer Krebs; Katri Pajusola; Raimo Tuuminen; Kari Alitalo; Karl B Lemström
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-06-26
Journal Detail:
Title:  The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation     Volume:  29     ISSN:  1557-3117     ISO Abbreviation:  J. Heart Lung Transplant.     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-08-23     Completed Date:  2010-12-30     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9102703     Medline TA:  J Heart Lung Transplant     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1058-66     Citation Subset:  IM    
Copyright Information:
Copyright 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
Affiliation:
Cardiopulmonary Research Group, Transplantation Laboratory, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
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MeSH Terms
Descriptor/Qualifier:
Abdomen
Animals
Apoptosis
Carbonic Anhydrases / metabolism
Gene Therapy*
Gene Transfer Techniques*
Graft Rejection / pathology
Heart Transplantation / immunology,  methods,  pathology*
Hypoxia-Inducible Factor 1, alpha Subunit / genetics*,  metabolism
Mice
Myocytes, Cardiac / drug effects,  pathology
Postoperative Complications / pathology
RNA, Messenger / genetics
Rats
Rats, Inbred Strains
Rats, Inbred WF
Transplantation, Heterotopic
Transplantation, Homologous / immunology,  pathology
Chemical
Reg. No./Substance:
0/Hif1a protein, rat; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/RNA, Messenger; EC 4.2.1.1/Carbonic Anhydrases; EC 4.2.1.1/carbonic anhydrase IX, rat

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