X-linked inhibitor of apoptosis protein-mediated attenuation of apoptosis, using a novel cardiac-enhanced adeno-associated viral vector.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Piacentino, V; Milano, CA; Bolanos, M; Schroder, J; Messina, E; Cockrell, AS; Jones, E; Krol, A; Bursac, N; Mao, L; Devi, GR; Samulski, RJ; Bowles, DE

Published Date

  • June 2012

Published In

Volume / Issue

  • 23 / 6

Start / End Page

  • 635 - 646

PubMed ID

  • 22339372

Pubmed Central ID

  • 22339372

Electronic International Standard Serial Number (EISSN)

  • 1557-7422

International Standard Serial Number (ISSN)

  • 1043-0342

Digital Object Identifier (DOI)

  • 10.1089/hum.2011.186

Language

  • eng