Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats

被引:115
作者
Janssens, SP
Bloch, KD
Nong, ZX
Gerard, RD
Zoldhelyi, P
Collen, D
机构
[1] KATHOLIEKE UNIV LEUVEN, CARDIAC UNIT, B-3000 LOUVAIN, BELGIUM
[2] HARVARD UNIV, MASSACHUSETTS GEN HOSP, SCH MED, CARDIOVASC RES CTR, BOSTON, MA 02115 USA
关键词
adenovirus; guanylate cyclase; hypoxia; pulmonary hypertension; gene therapy;
D O I
10.1172/JCI118795
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Nitric oxide (NO), a vasodilator involved in the regulation of pulmonary vascular tone, is synthesized by a family of enzymes, nitric oxide synthases (NOS). To investigate whether adenoviral-mediated overexpression of constitutive endothelial NOS (ceNOS) would attenuate hypoxic pulmonary vasoconstriction, we aerosolized 3 x 10(9) plaque forming units of a recombinant adenovirus containing the ceNOS gene (AdCMVceNOS) into rat lungs. Four days after infection, transgene expression was confirmed using immunoblot techniques. Diffuse ceNOS immunostaining was detected in alveoli and medium-sized and small pulmonary vessels of AdCMVceNOS-transduced lungs. AdCMVceNOS-transduction was associated with an 86% increase in [H-3]arginine to [H-3]citrulline conversion and a rise in pulmonary cGMP levels from 7+/-1 to 59+/-9 pmol/mg protein in lungs from AdCMVceNOS versus control rats, (P < 0.05). During acute hypoxia (FIO2 = 0.10) for 25 min, mean pulmonary artery pressure (PAP) increased significantly from 17+/-1 to 27+/-1 mmHg in rats aerosolized with saline (n = 4) and from 18+1 to 28+/-1 mmHg in rats given an adenoviral vector expressing a nuclear-targeted beta-galactosidase gene (AdCMV beta gal, n = 8). In contrast, in AdCMVceNOS-transduced rats (n = 8) the hypoxia-induced increase in PAP was significantly attenuated (18+/-1 to 23+/-2 mmHg). Systemic blood pressure was not affected by aerosol gene transfer. Thus, adenoviral-mediated ceNOS gene transfer to rat lungs increases ceNOS expression and activity, and reduces acute hypoxic pulmonary vasoconstriction. Aerosolized recombinant adenovirus overexpressing vasodilatory proteins can act as a selective pulmonary vasodilator and may hold promise as a future therapeutic strategy for pulmonary hypertension.
引用
收藏
页码:317 / 324
页数:8
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