X-Linked Inhibitor of Apoptosis Protein-Mediated Attenuation of Apoptosis, Using a Novel Cardiac-Enhanced Adeno-Associated Viral Vector
| Autor: | Edward E. Jones, Adam S. Cockrell, Ava Krol, R. Jude Samulski, Dawn E. Bowles, Jacob N. Schroder, Lan Mao, Carmelo A. Milano, Emily L. Messina, Nenad Bursac, Gayathri R. Devi, Valentino Piacentino, Michael Bolanos |
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| Rok vydání: | 2012 |
| Předmět: |
Transgene
Genetic enhancement Genetic Vectors Apoptosis X-Linked Inhibitor of Apoptosis Protein Biology Inhibitor of apoptosis Viral vector Mice Genetics medicine Animals Humans Myocyte Myocytes Cardiac Molecular Biology Research Articles Heart Failure Dependovirus medicine.disease Rats XIAP Heart failure Immunology Cancer research Molecular Medicine |
| Zdroj: | Human Gene Therapy. 23:635-646 |
| ISSN: | 1557-7422 1043-0342 |
| DOI: | 10.1089/hum.2011.186 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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