Circulation Research, Vol 73, 205-209, Copyright © 1993 by American Heart Association

ARTICLES

Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life

M Yoshizumi, MA Perrella, JC Burnett Jr and ME Lee
Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, MA 02115.

Nitric oxide (NO), which accounts for the biological properties of endothelium-derived relaxing factor, is generated by NO synthase (NOS). The vascular endothelium contains two types of NOS: one is constitutively expressed (cNOS), and the other is inducible. Endothelium-mediated vasorelaxation is impaired in atherosclerotic vessels. To determine whether tumor necrosis factor (TNF)-alpha, which is commonly found in atherosclerotic lesions, has an effect on NOS message, we measured cNOS mRNA levels in TNF-treated human umbilical vein endothelial cells (HUVECs) by RNA blot analysis with a cNOS cDNA probe. TNF-alpha markedly reduced cNOS mRNA levels in HUVECs in a dose- and time-dependent manner. In response to 3 ng/mL TNF-alpha, cNOS mRNA levels began to decrease at 4 hours and diminished to only 5% of control levels at 24 hours. As little as 0.1 ng/mL TNF-alpha reduced cNOS mRNA levels by 50%. This reduction in cNOS message in response to TNF-alpha depended on protein synthesis as it was blocked by cycloheximide. In nuclear runoff experiments, TNF-alpha did not change the rate of cNOS gene transcription. cNOS mRNA is very stable under basal conditions, with a half-life of 48 hours; however, treatment with TNF-alpha shortened this half-life to 3 hours. TNF-alpha thus appears to decrease cNOS mRNA levels by increasing the rate of mRNA degradation. TNF-induced reductions in cNOS mRNA levels may have an important effect on impaired endothelium-mediated vasorelaxation in atherosclerosis.

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				A.C. Mendes Ribeiro, T.M.C. Brunini, J.C. Ellory, and G.E. Mann Abnormalities in L-arginine transport and nitric oxide biosynthesis in chronic renal and heart failure Cardiovasc Res, March 1, 2001; 49(4): 697 - 712. [Abstract] [Full Text] [PDF]

				X.-W. QU, H. WANG, I. G. DE PLAEN, R. A. ROZENFELD, and W. HSUEH Neuronal nitric oxide synthase (NOS) regulates the expression of inducible NOS in rat small intestine via modulation of nuclear factor kappa B FASEB J, February 1, 2001; 15(2): 439 - 446. [Abstract] [Full Text] [PDF]

				X. L. Ma, F. Gao, J. Chen, T. A. Christopher, B. L. Lopez, E. H. Ohlstein, and T.-L. Yue Endothelial protective and antishock effects of a selective estrogen receptor modulator in rats Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H876 - H884. [Abstract] [Full Text] [PDF]

				T. Najarian, A. M. Marrache, I. Dumont, P. Hardy, M. H. Beauchamp, X. Hou, K. Peri, F. Gobeil Jr, D. R. Varma, and S. Chemtob Prolonged Hypercapnia-Evoked Cerebral Hyperemia via K+ Channel- and Prostaglandin E2-Dependent Endothelial Nitric Oxide Synthase Induction Circ. Res., December 8, 2000; 87(12): 1149 - 1156. [Abstract] [Full Text] [PDF]

				X. L. Ma, F. Gao, C.-L. Yao, J. Chen, B. L. Lopez, T. A. Christopher, J. Disa, J.-L. Gu, E. H. Ohlstein, and T.-L. Yue Nitric Oxide Stimulatory and Endothelial Protective Effects of Idoxifene, a Selective Estrogen Receptor Modulator, in the Splanchnic Artery of the Ovariectomized Rat J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 786 - 792. [Abstract] [Full Text]

				P.J. Pugh, K.M. English, T.H. Jones, and K.S. Channer Testosterone: a natural tonic for the failing heart? QJM, October 1, 2000; 93(10): 689 - 694. [Full Text] [PDF]

				M. M. ARRIERO, J. A. RODRÍGUEZ-FEO, A. CELDRÁN, L. S. D. MIGUEL, F. GONZÁLEZ-FERNÁNDEZ, J. FORTES, A. REYERO, O. FRIEYRO, J. C. D. L. PINTA, A. FRANCO, et al. Expression of Endothelial Nitric Oxide Synthase in Human Peritoneal Tissue: Regulation by Escherichia Coli Lipopolysaccharide J. Am. Soc. Nephrol., October 1, 2000; 11(10): 1848 - 1856. [Abstract] [Full Text]

				P. Hardy, I. Dumont, M. Bhattacharya, X. Hou, P. Lachapelle, D. R. Varma, and S. Chemtob Oxidants, nitric oxide and prostanoids in the developing ocular vasculature: a basis for ischemic retinopathy Cardiovasc Res, August 18, 2000; 47(3): 489 - 509. [Abstract] [Full Text] [PDF]

				H. Macarthur, T. C. Westfall, D. P. Riley, T. P. Misko, and D. Salvemini Inactivation of catecholamines by superoxide gives new insights on the pathogenesis of septic shock PNAS, August 15, 2000; 97(17): 9753 - 9758. [Abstract] [Full Text] [PDF]

				L. I Romero, D.-N. Zhang, J. P Cooke, H.-K. V Ho, E. Avalos, R. Herrera, and G S. Herron Differential expression of nitric oxide by dermal microvascular endothelial cells from patients with scleroderma Vascular Medicine, August 1, 2000; 5(3): 147 - 158. [Abstract] [PDF]

				W.S. Weintraub and D.G. Harrison C-reactive protein, inflammation and atherosclerosis: do we really understand it yet? Eur. Heart J., June 2, 2000; 21(12): 958 - 960. [PDF]

				N. C. Gocan, J. A. Scott, and K. Tyml Nitric oxide produced via neuronal NOS may impair vasodilatation in septic rat skeletal muscle Am J Physiol Heart Circ Physiol, May 1, 2000; 278(5): H1480 - H1489. [Abstract] [Full Text] [PDF]

				A.-M. Teichert, T. L. Miller, S. C. Tai, Y. Wang, X. Bei, G. B. Robb, M. J. Phillips, and P. A. Marsden In vivo expression profile of an endothelial nitric oxide synthase promoter-reporter transgene Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1352 - H1361. [Abstract] [Full Text] [PDF]

				H. Li and U. Förstermann Structure-Activity Relationship of Staurosporine Analogs in Regulating Expression of Endothelial Nitric-Oxide Synthase Gene Mol. Pharmacol., March 1, 2000; 57(3): 427 - 435. [Abstract] [Full Text]

				G. R. Drummond, H. Cai, M. E. Davis, S. Ramasamy, and D. G. Harrison Transcriptional and Posttranscriptional Regulation of Endothelial Nitric Oxide Synthase Expression by Hydrogen Peroxide Circ. Res., February 18, 2000; 86(3): 347 - 354. [Abstract] [Full Text] [PDF]

				A. Rojas, S. Romay, D. Gonzalez, B. Herrera, R. Delgado, and K. Otero Regulation of Endothelial Nitric Oxide Synthase Expression by Albumin-Derived Advanced Glycosylation End Products Circ. Res., February 18, 2000; 86 (3): e50 - e54. [Abstract] [Full Text] [PDF]

				K. Kuboki, Z. Y. Jiang, N. Takahara, S. W. Ha, M. Igarashi, T. Yamauchi, E. P. Feener, T. P. Herbert, C. J. Rhodes, and G. L. King Regulation of Endothelial Constitutive Nitric Oxide Synthase Gene Expression in Endothelial Cells and In Vivo : A Specific Vascular Action of Insulin Circulation, February 15, 2000; 101(6): 676 - 681. [Abstract] [Full Text] [PDF]

				J. Navarro-Antolin, J. Rey-Campos, and S. Lamas Transcriptional Induction of Endothelial Nitric Oxide Gene by Cyclosporine A. A ROLE FOR ACTIVATOR PROTEIN-1 J. Biol. Chem., February 4, 2000; 275(5): 3075 - 3080. [Abstract] [Full Text] [PDF]