Adenovirus-mediated overexpression of extracellular superoxide dismutase improves endothelial dysfunction in a rat model of hypertension.
Gene transfer may be appropriate for therapeutic protocols targeted at the vascular endothelium. Endothelial dysfunction is the principal phenotype associated with atherosclerosis and hypertension. Oxidative stress has been implicated in the development of endothelial dysfunction. We have explored the ability of overexpressing anti-oxidant genes (superoxide dismutases; SODs) in vitro and in vivo to assess their potential for reversing endothelial dysfunction in a rat model, the stroke-prone spontaneously hypertensive rat (SHRSP). Western blotting and immunofluorescence assays in vitro showed efficient overexpression of MnSOD and ECSOD with respect to localisation to the mitochondria and extracellular surface, respectively. Transgene functional activity was quantified with SOD activity assays. MnSOD and ECSOD overexpression in intact SHRSP vessels in vivo led to endothelial and adventitial overexpression. Pharmacological assessment of transduced vessels following in vivo delivery by basal NO availability quantification demonstrated that the "null" adenovirus and MnSOD adenovirus did not significantly increase NO availability. However, AdECSOD-treated carotid arteries showed a significant increase in NO availability (1.91 +/- 0.04 versus 0.75 +/- 0.08 g/g, n = 6, P = 0.029). In summary, efficient overexpression of ECSOD, but not MnSOD in vivo, results in improved endothelial function in a rat model of hypertension and has important implications for the development of endothelial-based vascular gene therapy.
Fennell
J P
JP
BHF Blood Pressure Group, Department of Medicine and Therapeutics, University of Glasgow, Glasgow, UK.
Brosnan
M J
MJ
Frater
A J
AJ
Hamilton
C A
CA
Alexander
M Y
MY
Nicklin
S A
SA
Heistad
D D
DD
Baker
A H
AH
Dominiczak
A F
AF
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000503:physiopathology*; D016166:Free Radical Scavengers / Q000378:metabolism*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000627:therapeutic use; D006973:Hypertension / Q000201:enzymology / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*
D016166:Free Radical Scavengers; D013482:Superoxide Dismutase