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    
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.
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.
Cardiopulmonary Research Group, Transplantation Laboratory, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
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MeSH Terms
Carbonic Anhydrases / metabolism
Gene Therapy*
Gene Transfer Techniques*
Graft Rejection / pathology
Heart Transplantation / immunology,  methods,  pathology*
Hypoxia-Inducible Factor 1, alpha Subunit / genetics*,  metabolism
Myocytes, Cardiac / drug effects,  pathology
Postoperative Complications / pathology
RNA, Messenger / genetics
Rats, Inbred Strains
Rats, Inbred WF
Transplantation, Heterotopic
Transplantation, Homologous / immunology,  pathology
Reg. No./Substance:
0/Hif1a protein, rat; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/RNA, Messenger; EC Anhydrases; EC anhydrase IX, rat

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