Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats
Stefan P. Janssens, Kenneth D. Bloch, Zengxuan Nong, Robert D. Gerard, Pierre Zoldhelyi, Desire Collen
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 109 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 [3H]arginine to [3H]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 β-galactosidase gene (AdCMVβgal, 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.
Journal of Clinical Investigation
https://doi.org/10.1172/JCI118795
Published - Jul 15 1996
10.1172/JCI118795
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Nitric Oxide Synthase Type III Medicine & Life Sciences 100%
Vasoconstriction Medicine & Life Sciences 89%
Vasodilator Agents Medicine & Life Sciences 17%
Adenoviridae Medicine & Life Sciences 17%
Pulmonary Artery Medicine & Life Sciences 16%
Hypoxia Medicine & Life Sciences 13%
Janssens, S. P., Bloch, K. D., Nong, Z., Gerard, R. D., Zoldhelyi, P., & Collen, D. (1996). Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats. Journal of Clinical Investigation, 98(2), 317-324. https://doi.org/10.1172/JCI118795
Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats. / Janssens, Stefan P.; Bloch, Kenneth D.; Nong, Zengxuan et al.
In: Journal of Clinical Investigation, Vol. 98, No. 2, 15.07.1996, p. 317-324.
Janssens, SP, Bloch, KD, Nong, Z, Gerard, RD, Zoldhelyi, P & Collen, D 1996, 'Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats', Journal of Clinical Investigation, vol. 98, no. 2, pp. 317-324. https://doi.org/10.1172/JCI118795
Janssens SP, Bloch KD, Nong Z, Gerard RD, Zoldhelyi P, Collen D. Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats. Journal of Clinical Investigation. 1996 Jul 15;98(2):317-324. doi: 10.1172/JCI118795
Janssens, Stefan P. ; Bloch, Kenneth D. ; Nong, Zengxuan et al. / Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats. In: Journal of Clinical Investigation. 1996 ; Vol. 98, No. 2. pp. 317-324.
@article{821fccc594d341d99fe67cb3765ec661,
title = "Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats",
abstract = "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 109 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 [3H]arginine to [3H]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 β-galactosidase gene (AdCMVβgal, 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.",
keywords = "adenovirus, gene therapy, guanylate cyclase, hypoxia, pulmonary hypertension",
author = "Janssens, {Stefan P.} and Bloch, {Kenneth D.} and Zengxuan Nong and Gerard, {Robert D.} and Pierre Zoldhelyi and Desire Collen",
doi = "10.1172/JCI118795",
journal = "Journal of Clinical Investigation",
publisher = "The American Society for Clinical Investigation",
T1 - Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats
AU - Janssens, Stefan P.
AU - Bloch, Kenneth D.
AU - Nong, Zengxuan
AU - Gerard, Robert D.
AU - Zoldhelyi, Pierre
AU - Collen, Desire
N2 - 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 109 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 [3H]arginine to [3H]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 β-galactosidase gene (AdCMVβgal, 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.
AB - 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 109 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 [3H]arginine to [3H]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 β-galactosidase gene (AdCMVβgal, 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.
KW - adenovirus
KW - gene therapy
KW - guanylate cyclase
KW - hypoxia
KW - pulmonary hypertension
U2 - 10.1172/JCI118795
DO - 10.1172/JCI118795
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation