title: Effect of bortezomib on the efficacy of AAV9.SERCA2a treatment to preserve cardiac function in a rat pressure-overload model of heart failure.
abstract: Adeno-associated virus (AAV)-based vectors are promising vehicles for therapeutic gene delivery, including for the treatment for heart failure. It has been demonstrated for each of the AAV serotypes 1 through 8 that inhibition of the proteasome results in increased transduction efficiencies. For AAV9, however, the effect of proteasome inhibitors on in vivo transduction has until now not been evaluated. Here we demonstrate, in a well-established rodent heart failure model, that concurrent treatment with the proteasome inhibitor bortezomib does not enhance the efficacy of AAV9.SERCA2a to improve cardiac function as examined by echocardiography and pressure volume analysis. Western blot analysis of SERCA2a protein and reverse transcription-PCR of SERCA2a mRNA demonstrated that bortezomib had no effect on either endogenous rat SERCA2a levels nor on expression levels of human SERCA2a delivered by AAV9.SERCA2a. Similarly, the number of AAV9 genomes in heart samples was unaffected by bortezomib treatment. Interestingly, whereas transduction of HeLa cells and neonatal rat cardiomyocytes by AAV9 was stimulated by bortezomib, transduction of adult rat cardiomyocytes was inhibited. These results indicate an organ/cell-type-specific effect of proteasome inhibition on AAV9 transduction. A future detailed analysis of the underlying molecular mechanisms promises to facilitate the development of improved AAV vectors.
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Antoine H
authors.initials: AH
authors.lastname: Chaanine
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Nonnenmacher
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Erik
authors.initials: E
authors.lastname: Kohlbrenner
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Dongzhu
authors.initials: D
authors.lastname: Jin
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Kovacic
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Fadi G
authors.initials: FG
authors.lastname: Akar
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Thomas
authors.initials: T
authors.lastname: Weber
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors; D006333:Heart Failure / Q000235:genetics / Q000628:therapy*; D006801:Humans; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D011719:Pyrazines / Q000008:administration & dosage*; D051381:Rats; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000096:biosynthesis
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases