title: X-linked inhibitor of apoptosis protein-mediated attenuation of apoptosis, using a novel cardiac-enhanced adeno-associated viral vector.
abstract: 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.affiliation: Cardiothoracic Division, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Valentino
authors.initials: V
authors.lastname: Piacentino
authors.forename: Carmelo A
authors.initials: CA
authors.lastname: Milano
authors.forename: Michael
authors.initials: M
authors.lastname: Bolanos
authors.forename: Jacob
authors.initials: J
authors.lastname: Schroder
authors.forename: Emily
authors.initials: E
authors.lastname: Messina
authors.forename: Adam S
authors.initials: AS
authors.lastname: Cockrell
authors.forename: Edward
authors.initials: E
authors.lastname: Jones
authors.forename: Ava
authors.initials: A
authors.lastname: Krol
authors.forename: Nenad
authors.initials: N
authors.lastname: Bursac
authors.forename: Lan
authors.initials: L
authors.lastname: Mao
authors.forename: Gayathri R
authors.initials: GR
authors.lastname: Devi
authors.forename: R Jude
authors.initials: RJ
authors.lastname: Samulski
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Bowles
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D000229:Dependovirus / Q000235:genetics; D005822:Genetic Vectors; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000821:virology; D051381:Rats; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics*
chemical_list: D051636:X-Linked Inhibitor of Apoptosis Protein