Vascular endothelium has a local anti-adenovirus vector system and glucocorticoid optimizes its gene transduction.
OBJECTIVE
Although adenovirus is a powerful tool for vascular research and therapy, endothelial impairment after infection has been reported. We investigated the mechanisms of this impairment and the effect of dexamethasone (DEX) on gene transfer into the vascular endothelial cells.


RESULTS
Beta-galactosidase gene encoding adenovirus vector (beta-gal-Ad) (7.5 x 10(8) plaque-forming units/mL) transduced beta-gal into the rabbit organ-cultured pulmonary endothelium, followed by an apoptosis and an impairment of endothelium-dependent relaxation (EDR). Endothelial cell infected by beta-gal-Ad expressed proinflammatory genes mRNAs and suppressed endothelial nitric oxide synthase (eNOS) mRNA. Treatment with DEX dramatically increased beta-gal protein expression in the endothelium, attenuated beta-gal-Ad-induced apoptosis, and prevented the impairment of EDR. DEX also suppressed the mRNAs expressions of proinflammatory genes and recovered eNOS mRNA expression in organ-cultured vascular endothelium. In addition, we confirmed the DEX's beneficial effects in an endothelial cell line (in vitro) and rat femoral artery (in vivo) experiments.


CONCLUSIONS
These results suggest that adenovirus vector induces host-immune responses and apoptosis in vascular endothelial cells. DEX is found to be a useful and potent tool to prevent the Ad-induced impairments of the endothelium and to optimize gene expression efficiency by adenovirus vector at the protein translation level in both in vitro and in vivo experiments.
Murata
Takahisa
T
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
Hori
Masatoshi
M
Lee
Sheng
S
Nakamura
Akio
A
Kohama
Kazuhiro
K
Karaki
Hideaki
H
Ozaki
Hiroshi
H
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000257:Adenoviridae Infections / Q000276:immunology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016923:Cell Death / Q000276:immunology; D002478:Cells, Cultured; D003360:Cosmids / Q000493:pharmacokinetics; D016572:Cyclosporine / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000821:virology*; D005263:Femoral Artery / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D009924:Organ Culture Techniques; D011817:Rabbits; D014161:Transduction, Genetic / Q000379:methods*; D019076:Transgenes / Q000187:drug effects / Q000235:genetics; D014471:Umbilical Veins / Q000166:cytology; D014657:Vasculitis / Q000276:immunology / Q000821:virology*; D001616:beta-Galactosidase / Q000235:genetics
D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D009569:Nitric Oxide; D003907:Dexamethasone; D016572:Cyclosporine; D001616:beta-Galactosidase