title: Preservation of cardiac function in left ventricle cardiac hypertrophy using an AAV vector which provides VEGF-A expression in response to p53.
abstract: Here we present the application of our adeno-associated virus (AAV2) vector where transgene expression is driven by a synthetic, p53-responsive promoter, termed PG, used to supply human vascular endothelial growth factor-A165 (VEGF-A). Thus, p53 is harnessed to promote the beneficial expression of VEGF-A encoded by the AAVPG vector, bypassing the negative effect of p53 on HIF-1α which occurs during cardiac hypertrophy. Wistar rats were submitted to pressure overload induced by thoracic aorta coarctation (TAC) with or without concomitant gene therapy (intramuscular delivery in the left ventricle). After 12 weeks, rats receiving AAVPG-VEGF gene therapy were compared to those that did not, revealing significantly improved cardiac function under hemodynamic stress, lack of fibrosis and reversal of capillary rarefaction. With these functional assays, we have demonstrated that application of the AAVPG-VEGF vector under physiologic conditions known to stimulate p53 resulted in the preservation of cardiac performance.
authors.affiliation: Viral Vector Laboratory, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil; Laboratory of Genetics and Molecular Cardiology/LIM13, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Marcio C
authors.initials: MC
authors.lastname: Bajgelman
authors.affiliation: Laboratory of Genetics and Molecular Cardiology/LIM13, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Dos Santos
authors.affiliation: Laboratory of Genetics and Molecular Cardiology/LIM13, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Gustavo J J
authors.initials: GJJ
authors.lastname: Silva
authors.affiliation: Laboratory of Genetics and Molecular Cardiology/LIM13, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Juliana
authors.initials: J
authors.lastname: Nakamuta
authors.affiliation: Hypertension Unit, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Raquel A
authors.initials: RA
authors.lastname: Sirvente
authors.affiliation: Laboratory of Genetics and Molecular Cardiology/LIM13, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Marcio
authors.initials: M
authors.lastname: Chaves
authors.affiliation: Laboratory of Genetics and Molecular Cardiology/LIM13, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: José Eduardo
authors.initials: JE
authors.lastname: Krieger
authors.affiliation: Viral Vector Laboratory, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil; Laboratory of Genetics and Molecular Cardiology/LIM13, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil. Electronic address: bstrauss@usp.br.
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Strauss
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics* / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A
keywords: AAV; Cardiac hypertrophy; HIF1; VEGF; p53