Nitric oxide (NO) is believed to interfere with cell proliferation, although its mechanism of cytostatic action is largely unknown. This view is based on the observations that NO donor agents or induction of NO synthase in cultured cells is associated with the concomitant attenuation of cell proliferation. We have found that N/G-hydroxy-L- arginine (NOHA), an intermediate in the oxidation of arginine to NO + citrulline, is synthesized and released from cells in culture. NOHA is a potent competitive inhibitor or arginase (Ki = 10 muM) and turns off production of ornithine + urea in cells. Ornithine is the precursor to putrescine and other polyamines required for cell proliferation. We have also found that NO inhibits ornithine decarboxylase activity. The principal objective of the proposed research is to determine whether NO synthase, via the biologic actions of NOHA and NO, plays a physiological or pathophysiological role in regulating the growth of vascular smooth muscle cells and tumor cells, and to elucidate the mechanisms by which cell growth is inhibited. The central hypothesis that drives this proposal is that two products of the NO synthase reaction, NOHA and NO, function biologically to slow cell proliferation by inhibiting two sequential enzymatic steps (NOHA inhibits arginase; NO inhibits ornithine decarboxylase) in the pathway leading to the production of polyamines from arginine. These additional cytostatic mechanisms resulting from increased NO synthase activity would complement other known cytostatic mechanisms of NO such as guanylyl cyclase activation and cyclic GMP-mediated impairment of DNA synthesis. The two specific aims that will be taken to rigorously test the proposed hypothesis are: (a) to ascertain the mechanisms by which NOHA, NO and NO synthase activity interfere with cell proliferation under physiological or pathophysiological conditions and (b) to elucidate the mechanism by which NO inhibits ornithine decarboxylase. The proposed research should advance our understanding of the biological role of NO synthase in regulating cell proliferation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058433-02
Application #
6184223
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1999-04-01
Project End
2002-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
2
Fiscal Year
2000
Total Cost
$292,689
Indirect Cost
Name
University of California Los Angeles
Department
Pharmacology
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Napoli, Claudio; de Nigris, Filomena; Williams-Ignarro, Sharon et al. (2006) Nitric oxide and atherosclerosis: an update. Nitric Oxide 15:265-79
Sumi, Daigo; Ignarro, Louis J (2005) Sp1 transcription factor expression is regulated by estrogen-related receptor alpha1. Biochem Biophys Res Commun 328:165-72
Napoli, Claudio; Williams-Ignarro, Sharon; De Nigris, Filomena et al. (2004) Long-term combined beneficial effects of physical training and metabolic treatment on atherosclerosis in hypercholesterolemic mice. Proc Natl Acad Sci U S A 101:8797-802
Ongini, Ennio; Impagnatiello, Francesco; Bonazzi, Albino et al. (2004) Nitric oxide (NO)-releasing statin derivatives, a class of drugs showing enhanced antiproliferative and antiinflammatory properties. Proc Natl Acad Sci U S A 101:8497-502
Sumi, Daigo; Ignarro, Louis J (2004) Regulation of inducible nitric oxide synthase expression in advanced glycation end product-stimulated raw 264.7 cells: the role of heme oxygenase-1 and endogenous nitric oxide. Diabetes 53:1841-50
Napoli, Claudio; Ignarro, Louis J (2003) Nitric oxide-releasing drugs. Annu Rev Pharmacol Toxicol 43:97-123
de Nigris, Filomena; Lerman, Lilach O; Ignarro, Sharon Williams et al. (2003) Beneficial effects of antioxidants and L-arginine on oxidation-sensitive gene expression and endothelial NO synthase activity at sites of disturbed shear stress. Proc Natl Acad Sci U S A 100:1420-5
de Nigris, Filomena; Lerman, Amir; Ignarro, Louis J et al. (2003) Oxidation-sensitive mechanisms, vascular apoptosis and atherosclerosis. Trends Mol Med 9:351-9
Sumi, Daigo; Ignarro, Louis J (2003) Estrogen-related receptor alpha 1 up-regulates endothelial nitric oxide synthase expression. Proc Natl Acad Sci U S A 100:14451-6

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