Preservation of cardiac function in left ventricle cardiac hypertrophy using an AAV vector which provides VEGF-A expression in response to p53

Autor(es)

Bajgelman, Marcio C. ^{[1, 2]} ; dos Santos, Leonardo ^[2] ; Silva, Gustavo J. J. ^[2] ; Nakamuta, Juliana ^[2] ; Sirvente, Raquel A. ^[3] ; Chaves, Marcio ^[2] ; Krieger, Jose Eduardo ^[2] ; Strauss, Bryan E. ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sch Med, Inst Heart, Viral Vector Lab, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Sch Med, Inst Heart, Lab Genet & Mol Cardiol LIM13, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Sch Med, Inst Heart, Hypertens Unit, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: VIROLOGY; v. 476, p. 106-114, FEB 2015.
• Citações Web of Science: 10

Resumo

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-A(165) (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-1 alpha 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. (C) 2014 Elsevier Inc. All rights reserved. (AU)

• Processo FAPESP: 11/50911-4 - Elucidação dos mecanismos moleculares que mediam a resposta da células de melanoma para a atividade combinada das vias de p53/arf e ifnb
• Beneficiário: Bryan Eric Strauss
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 07/54480-2 - Desenvolvimento de uma nova estratégia baseada em terapia gênica por demanda para prevenir a deterioração da função cardíaca associada à hipertrofia
• Beneficiário: Marcio Chaim Bajgelman
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 07/50210-0 - Combinações estratégicas entre os promotores virais e transgenes destinadas a terapia gênica do câncer
• Beneficiário: Bryan Eric Strauss
• Linha de fomento: Auxílio à Pesquisa - Regular