Document Detail


X-linked inhibitor of apoptosis protein-mediated attenuation of apoptosis, using a novel cardiac-enhanced adeno-associated viral vector.
MedLine Citation:
PMID:  22339372     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Successful amelioration of cardiac dysfunction and heart failure through gene therapy approaches will require a transgene effective at attenuating myocardial injury, and subsequent remodeling, using an efficient and safe delivery vehicle. Our laboratory has established a well-curated, high-quality repository of human myocardial tissues that we use as a discovery engine to identify putative therapeutic transgene targets, as well as to better understand the molecular basis of human heart failure. By using this rare resource we were able to examine age- and sex-matched left ventricular samples from (1) end-stage failing human hearts and (2) nonfailing human hearts and were able to identify the X-linked inhibitor of apoptosis protein (XIAP) as a novel target for treating cardiac dysfunction. We demonstrate that XIAP is diminished in failing human hearts, indicating that this potent inhibitor of apoptosis may be central in protecting the human heart from cellular injury culminating in heart failure. Efforts to ameliorate heart failure through delivery of XIAP compelled the design of a novel adeno-associated viral (AAV) vector, termed SASTG, that achieves highly efficient transduction in mouse heart and in cultured neonatal rat cardiomyocytes. Increased XIAP expression achieved with the SASTG vector inhibits caspase-3/7 activity in neonatal cardiomyocytes after induction of apoptosis through three common cardiac stresses: protein kinase C-γ inhibition, hypoxia, or β-adrenergic receptor agonist. These studies demonstrate the potential benefit of XIAP to correct heart failure after highly efficient delivery to the heart with the rationally designed SASTG AAV vector.
Authors:
Valentino Piacentino; Carmelo A Milano; Michael Bolanos; Jacob Schroder; Emily Messina; Adam S Cockrell; Edward Jones; Ava Krol; Nenad Bursac; Lan Mao; Gayathri R Devi; R Jude Samulski; Dawn E Bowles
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-03-13
Journal Detail:
Title:  Human gene therapy     Volume:  23     ISSN:  1557-7422     ISO Abbreviation:  Hum. Gene Ther.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-07-12     Completed Date:  2012-12-03     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  9008950     Medline TA:  Hum Gene Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  635-46     Citation Subset:  IM    
Affiliation:
Cardiothoracic Division, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / genetics*
Dependovirus* / genetics
Genetic Vectors
Heart Failure / drug therapy
Humans
Mice
Myocytes, Cardiac / virology
Rats
X-Linked Inhibitor of Apoptosis Protein / genetics*
Grant Support
ID/Acronym/Agency:
5P01HL075443-04900/HL/NHLBI NIH HHS; 5R01HL072183-03/HL/NHLBI NIH HHS; HL-083342/HL/NHLBI NIH HHS; P01 HL066973/HL/NHLBI NIH HHS; R01 AI072176/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/X-Linked Inhibitor of Apoptosis Protein
Comments/Corrections

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