Adenovirus-mediated overexpression of extracellular superoxide dismutase improves endothelial dysfunction in a rat model of hypertension

被引:80
作者
Fennell, JP
Brosnan, MJ
Frater, AJ
Hamilton, CA
Alexander, MY
Nicklin, SA
Heistad, DD
Baker, AH
Dominiczak, AF [1 ]
机构
[1] Univ Glasgow, Western Infirm, Dept Med & Therapeut, BHF Blood Pressure Grp, Glasgow G11 6NT, Lanark, Scotland
[2] Univ Iowa, Coll Med, Dept Internal Med, Iowa City, IA 52242 USA
[3] Univ Iowa, Coll Med, Program Gene Therapy, Iowa City, IA 52242 USA
[4] VA Med Ctr, Iowa City, IA USA
关键词
adenovirus; gene transfer; superoxide dismutase; nitric oxide; SHRSP;
D O I
10.1038/sj.gt.3301633
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:110 / 117
页数:8
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