Adenoviral transfer of the inducible nitric oxide synthase gene blocks endothelial cell apoptosis

Edith Tzeng*, Young Myeong Kim, Bruce R. Pitt, Alena Lizonova, Imre Kovesdi, Timothy R. Billiar

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

142 Scopus citations

Abstract

Background. We have previously reported that vascular inducible nitric oxide synthase (iNOS) gene transfer inhibits injury-induced intimal hyperplasia in vitro and in vivo. One mechanism by which NO may prevent intimal hyperplasia is by preserving the endothelium or promoting its regeneration. To study this possibility we examined the effect of iNOS gene transfer on endothelial cell (EC) proliferation and viability. Methods. An adenoviral vector (AdiNOS) containing the human iNOS cDNA was constructed and used to infect cultured sheep arterial ECs. NO production was measured, and the effects of continuous NO exposure on EC proliferation, viability, and apoptosis were evaluated. Results. AdiNOS-infected ECs produced 25- to 100- fold more NO than control (AdlacZ) infected cells as measured by nitrite accumulation. This increased NO synthesis did not inhibit EC proliferation as reflected by tritiated thymidine incorporation. Chromium 51 release assay revealed that EC viability was also unaffected by AdiNOS infection and NO synthesis. In addition, prolonged exposure to NO synthesis did not induce EC apoptosis. Instead, NO inhibited lipopolysaccharide-induced apoptosis in these cells by reducing caspase-3-like protease activity. Conclusions. Vascular iNOS gene transfer, while inhibiting smooth muscle cell proliferation, does not impair EC mitogenesis or viability. Augmented NO synthesis may also protect ECs against apogenic stimuli such as lipopolysaccharide. Therefore iNOS gene transfer may promote endothelial regeneration and can perhaps accelerate vascular healing.

Original languageEnglish
Pages (from-to)255-263
Number of pages9
JournalSurgery
Volume122
Issue number2
DOIs
StatePublished - Aug 1997

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