| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1Vascular Physiology Group and 2Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico; and 3Centers for Developmental Pharmacology and Toxicology, Gene Therapy, and Cell and Vascular Biology, Columbus Children's Research Institute, Department of Pediatrics, The Ohio State University, Columbus, Ohio
Submitted 29 March 2005 ; accepted in final form 4 September 2005
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 also can 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, we transfected bovine pulmonary arterial endothelial cells (bPAEC) with an adenoviral vector containing the gene for iNOS (AdiNOS). As expected, NO production in AdiNOS bPAEC was substantially greater than in control bPAEC. Although 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 N
-nitro-L-arginine methyl ester 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 not only be beneficial through NO-mediated pulmonary vasodilation but also may decrease vascular remodeling by limiting L-Orn production by native arginase.
nitric oxide; urea; pulmonary hypertension; pulmonary vascular remodeling
This article has been cited by other articles:
|
|
 |
|
  R. Chang, L. G. Chicoine, H. Cui, N. L. Kanagy, B. R. Walker, Y. Liu, B. K. English, and L. D. Nelin Cytokine-induced arginase activity in pulmonary endothelial cells is dependent on Src family tyrosine kinase activity Am J Physiol Lung Cell Mol Physiol, October 1, 2008; 295(4): L688 - L697. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Santhanam, H. K. Lim, H. K. Lim, V. Miriel, T. Brown, M. Patel, S. Balanson, S. Ryoo, M. Anderson, K. Irani, et al. Inducible NO Synthase Dependent S-Nitrosylation and Activation of Arginase1 Contribute to Age-Related Endothelial Dysfunction Circ. Res., September 28, 2007; 101(7): 692 - 702. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. D. Nelin, X. Wang, Q. Zhao, L. G. Chicoine, T. L. Young, D. M. Hatch, B. K. English, and Y. Liu MKP-1 switches arginine metabolism from nitric oxide synthase to arginase following endotoxin challenge Am J Physiol Cell Physiol, August 1, 2007; 293(2): C632 - C640. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. C. Duling, T. W. Cherng, J. R. Griego, M. F. Perrine, and N. L. Kanagy Loss of {alpha}2B-adrenoceptors increases magnitude of hypertension following nitric oxide synthase inhibition Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2403 - H2408. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
