Phosphodiesterase inhibitor-mediated potentiation of adenovirus delivery to myocardium.
Current gene therapy models are limited by inadequate vector delivery. Increases in microvascular permeability have been shown to improve adenovirus-mediated gene transfer to ex vivo and in vivo models. We explored the intracellular mechanism underlying the permeabilizing effects of vascular endothelial growth factor (VEGF). Using an ex vivo model of coronary perfusion in rabbits, we found a dose-response relationship between VEGF and the efficiency of adenoviral gene transfer. Inhibitors of nitric oxide synthase and guanylate cyclase prevented the VEGF effect, and analogues of nitric oxide and cGMP mimicked the effect. Co-administration of phosphodiesterase-5 inhibitors and VEGF caused a synergistic increase in gene delivery. These results can be readily applied to existing models to further optimize vector delivery for gene therapy.
Nagata
K
K
Institute of Molecular Cardiobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. kdonahue@jhmi.edu
Marbán
E
E
Lawrence
J H
JH
Donahue
J K
JK
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000260:Adenoviruses, Human; D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004357:Drug Synergism; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D005822:Genetic Vectors; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D008222:Lymphokines / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000378:metabolism / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D005996:Nitroglycerin / Q000378:metabolism / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines; D011688:Purinones / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D000068677:Sildenafil Citrate; D013450:Sulfones; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D001616:beta-Galactosidase / Q000235:genetics; D019323:omega-N-Methylarginine / Q000494:pharmacology
D016228:Endothelial Growth Factors; D007546:Isoquinolines; D008222:Lymphokines; D020030:Nitric Oxide Donors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011688:Purinones; D011725:Pyridines; D013450:Sulfones; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019323:omega-N-Methylarginine; C016276:8-bromocyclic GMP; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D001616:beta-Galactosidase; D006162:Guanylate Cyclase; D005996:Nitroglycerin; C011145:zaprinast; D006152:Cyclic GMP; C412889:T 1032