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1 Vascular Physiology Group, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
2 Vascular Physiology Group, University of New Mexico Health Sciences Center, Albuquerque, NM, USA; Department of Pediatrics, Ohio State University, Columbus, OH, USA
3 Department of Pediatrics, Ohio State University, Columbus, OH, USA
4 Centers for Developmental Pharmacology and Toxicology; Gene Therapy and Cell and Vascular Biology, Columbus Children's Reserach Institute, Columbus, OH, USA
* To whom correspondence should be addressed. E-mail: NelinL{at}pediatrics.ohio-state.edu.
Nitric oxide (NO) is a vasodilator produced from L-arginine (L-arg) by NO synthase (NOS). Gene therapy for hypertensive disorders has been proposed using the inducible isoform of NOS (iNOS). L-arg can also be metabolized to urea and L-ornithine (L-orn) by arginase, and L-orn can be metabolized to proline and/or polyamines, which are vital for cellular proliferation. To determine the effect of iNOS gene transfer on arginase, bovine pulmonary arterial endothelial cells (bPAEC) were transfected with an adenoviral vector containing the gene for iNOS (AdiNOS). As expected, NO production in AdiNOS bPAEC was substantially greater than in control bPAEC. While urea production was significantly less in the AdiNOS bPAEC than in the control bPAEC, despite similar levels of arginase I protein. AdiNOS transfection of bPAEC had no effect on the uptake of L-arg. Inhibiting NO production with L-NAME increased urea production, and inhibiting urea production with L-valine increased nitrite production in AdiNOS bPAEC. The addition of L-arg to the medium increased urea production by AdiNOS bPAEC in a concentration-dependent manner. Thus, in these iNOS-transfected bPAEC, the transfected iNOS and native arginase compete for a common intracellular pool of L-arg. This competition for substrate resulted in impaired proliferation in the AdiNOS transfected bPAEC. These findings suggest that the use of iNOS gene therapy for pulmonary hypertensive disorders may be beneficial not only through NO-mediated pulmonary vasodilation, but also may decrease vascular remodeling by limiting L-orn production by native arginase.
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