Preventive effect of endothelial nitric oxide synthase gene transfer on chronic hypoxic pulmonary hypertension in rats

Abstract

Objective To investigate the preventive effect of endothelial nitric oxide synthase (eNOS) gene transfer on chronic hypoxic pulmonary hypertension (CHPH) in rats. Methods Twenty-four male Wistar rats were randomly divided into four groups with 6 rats in each group: normoxia group (group N). Hypoxia group (group H), hypoxia with LacZ group (group H-LacZ) and hypoxia with eNOS group (group H-eNOS). AdCMVceNOS, AdCMVLacZ or normal saline (NS) was injected intratracheally 3 days before the beginning of exposure to normoxia or hypoxia. Rats in group H-eNOS received 50 μl of AdCMVceNOS (5× 1012 pfu/L), rats in group H-LacZ received equal dose of AdCMVLacZ, rats in group N and group H received equal dose of NS. Hemodynamic parameters Cincluding mean systemic arterial pressure (MSAP), heart rate (HR) and mean pulmonary arterial pressure (MPAP)], pulmonary vascular remodeling (percentage of muscularized arteries in small pulmonary vessels) and right ventricular hypertrophy (ratio of right ventricle to left ventricle + septum weight) were measured after 2 weeks of exposure to normoxia or hypoxia. The expression of eNOS, cyclic guanosine monophosphate (cGMP) and nitric oxide (NO) level were also measured in lungs. Results The MPAP, right ventricular hypertrophy index and pulmonary vascular remodeling in rats in group H-eNOS were obviously lower than those in group H and H-LacZ, but higher than that in group N (all P＜0. 01). There was no significant difference with regard to HR and MSAP in rats in all groups (all P＞0. 05). The eNOS protein in group H and H-LacZ was obviously higher than that in group N, but obviously lower than that in group H-eNOS (all P＜0. 01). The NO level in rat lungs in group H and H-LacZ was obviously lower than that in group N, and value in group H-eNOS was higher than that in the other groups (P＜0. 05 or P＜0. 01). With regard to cGMP in rat lungs, there was no significant difference among group N, H and H-LacZ (all P＞0. 05), but they were all obviously lower than that in group H-eNOS (all P＜0. 01). Conclusion Intratracheal eNOS gene transfer upregulates the activity of eNOS protein, elevates the level of NO/cGMP in lungs, and alleviates CHPH in rats. Key words: recombinant adenovirus ; endothelial nitric oxide synthase ; gene transfer ; pulmonary hypertension ;