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

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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.

Original languageEnglish (US)
Pages (from-to)317-324
Number of pages8
JournalJournal of Clinical Investigation
Volume98
Issue number2
DOIs
StatePublished - Jul 15 1996

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Keywords

  • adenovirus
  • gene therapy
  • guanylate cyclase
  • hypoxia
  • pulmonary hypertension

ASJC Scopus subject areas

  • Medicine(all)

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