This Article Full Text Full Text (PDF) Data Supplement Data Supplement Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kalra, D. Articles by Mann, D. L. Search for Related Content PubMed PubMed Citation Articles by Kalra, D. Articles by Mann, D. L. Related Collections Congestive Cell signalling/signal transduction Gene expression Growth factors/cytokines Heart failure - basic studies

(Circulation. 2000;102:1302.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Nitric Oxide Provokes Tumor Necrosis Factor- Expression in Adult Feline Myocardium Through a cGMP-Dependent Pathway

Dinesh Kalra, MD; Georg Baumgarten, MD; Ziad Dibbs, MD; Yukihiro Seta, MD; Natarajan Sivasubramanian, PhD; Douglas L. Mann, MD

From the Winters Center for Heart Failure Research, Cardiology Section, Department of Medicine, Veterans Administration Medical Center and Baylor College of Medicine, Houston, Tex.

Correspondence to Douglas L. Mann, MD, Cardiology Research (151C), VA Medical Center, 2002 Holcombe Blvd, Houston, TX 77030. E-mail dmann{at}bcm.tmc.edu

Background—The mechanism(s) responsible for the persistent coexpression of tumor necrosis factor- (TNF-) and nitric oxide (NO) in the failing heart is unknown.

Methods and Results—To determine whether NO was sufficient to provoke TNF- biosynthesis, we examined the effects of an NO donor, S-nitroso-N-acetyl penicillamine (SNAP), in buffer-perfused Langendorff hearts. SNAP (1 µmol/L) treatment resulted in a time- and dose-dependent increase in myocardial TNF- mRNA and protein biosynthesis in adult cat hearts. The effects of SNAP were completely abrogated by a NO quenching agent, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (C-PTIO), and mimicked by sodium nitroprusside. Electrophoretic mobility shift assays demonstrated that SNAP treatment led to the rapid induction of nuclear factor kappa-beta (NF-B) but not AP-1. The importance of the cGMP pathway in terms of mediating NO-induced TNF- biosynthesis was shown by studies that demonstrated that 8-bromo-cGMP mimicked the effects of SNAP and that the effects of SNAP could be completely abrogated using a cGMP antagonist, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), or protein kinase G antagonist (Rp-8-Br-cGMPS). SNAP and 8-Br-cGMP were both sufficient to lead to the site-specific phosphorylation (serine 32) and degradation of IB in isolated cardiac myocytes. Finally, protein kinase G was sufficient to directly phosphorylate IB on serine 32, a critical step in the activation of NF-B.

Conclusions—These studies show that NO provokes TNF- biosynthesis through a cGMP-dependent pathway, which suggests that the coincident expression of TNF- and NO may foster self-sustaining positive autocrine/paracrine feedback inflammatory circuits within the failing heart.

Key Words: nitric oxide • tumor necrosis factor • cyclic GMP • NF-B • heart failure, congestive

This article has been cited by other articles:

				A. Steensberg, C. Keller, T. Hillig, C. Frosig, J. F. P. Wojtaszewski, B. K. Pedersen, H. Pilegaard, and M. Sander Nitric oxide production is a proximal signaling event controlling exercise-induced mRNA expression in human skeletal muscle FASEB J, September 1, 2007; 21(11): 2683 - 2694. [Abstract] [Full Text] [PDF]

				H.-F. Cheng, M.-Z. Zhang, and R. C. Harris Nitric oxide stimulates cyclooxygenase-2 in cultured cTAL cells through a p38-dependent pathway Am J Physiol Renal Physiol, June 1, 2006; 290(6): F1391 - F1397. [Abstract] [Full Text] [PDF]

				G. F. Tomaselli and D. P. Zipes What Causes Sudden Death in Heart Failure? Circ. Res., October 15, 2004; 95(8): 754 - 763. [Abstract] [Full Text] [PDF]

				K. Sekiguchi, X. Li, M. Coker, M. Flesch, P. M Barger, N. Sivasubramanian, and D. L Mann Cross-regulation between the renin-angiotensin system and inflammatory mediators in cardiac hypertrophy and failure Cardiovasc Res, August 15, 2004; 63(3): 433 - 442. [Abstract] [Full Text] [PDF]

				R. B. Pilz and D. E. Casteel Regulation of Gene Expression by Cyclic GMP Circ. Res., November 28, 2003; 93(11): 1034 - 1046. [Abstract] [Full Text] [PDF]

				L. Connelly, A. T. Jacobs, M. Palacios-Callender, S. Moncada, and A. J. Hobbs Macrophage Endothelial Nitric-oxide Synthase Autoregulates Cellular Activation and Pro-inflammatory Protein Expression J. Biol. Chem., July 11, 2003; 278(29): 26480 - 26487. [Abstract] [Full Text] [PDF]

				T. Peng, X. Lu, M. Lei, and Q. Feng Endothelial Nitric-oxide Synthase Enhances Lipopolysaccharide-stimulated Tumor Necrosis Factor-alpha Expression via cAMP-mediated p38 MAPK Pathway in Cardiomyocytes J. Biol. Chem., February 28, 2003; 278(10): 8099 - 8105. [Abstract] [Full Text] [PDF]

				D. L. Brutsaert Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity Physiol Rev, January 1, 2003; 83(1): 59 - 115. [Abstract] [Full Text] [PDF]

				D. L. Mann Inflammatory Mediators and the Failing Heart: Past, Present, and the Foreseeable Future Circ. Res., November 29, 2002; 91(11): 988 - 998. [Abstract] [Full Text] [PDF]

				H. Funakoshi, T. Kubota, N. Kawamura, Y. Machida, A. M. Feldman, H. Tsutsui, H. Shimokawa, and A. Takeshita Disruption of Inducible Nitric Oxide Synthase Improves {beta}-Adrenergic Inotropic Responsiveness but Not the Survival of Mice With Cytokine-Induced Cardiomyopathy Circ. Res., May 17, 2002; 90(9): 959 - 965. [Abstract] [Full Text] [PDF]

				M. Thielmann, H. Dorge, C. Martin, S. Belosjorow, U. Schwanke, A. van de Sand, I. Konietzka, A. Buchert, A. Kruger, R. Schulz, et al. Myocardial Dysfunction With Coronary Microembolization: Signal Transduction Through a Sequence of Nitric Oxide, Tumor Necrosis Factor-{alpha}, and Sphingosine Circ. Res., April 19, 2002; 90(7): 807 - 813. [Abstract] [Full Text] [PDF]

				G. Wright, I. S. Singh, J. D. Hasday, I. K. Farrance, G. Hall, A. S. Cross, and T. B. Rogers Endotoxin stress-response in cardiomyocytes: NF-kappa B activation and tumor necrosis factor-alpha expression Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H872 - H879. [Abstract] [Full Text] [PDF]

				G. Valen, Z.-q. Yan, and G.o. K. Hansson Nuclear factor kappa-B and the heart J. Am. Coll. Cardiol., August 1, 2001; 38(2): 307 - 314. [Abstract] [Full Text] [PDF]

				M. Thielmann, H. Dorge, C. Martin, S. Belosjorow, U. Schwanke, A. van de Sand, I. Konietzka, A. Buchert, A. Kruger, R. Schulz, et al. Myocardial Dysfunction With Coronary Microembolization: Signal Transduction Through a Sequence of Nitric Oxide, Tumor Necrosis Factor-{alpha}, and Sphingosine Circ. Res., April 19, 2002; 90(7): 807 - 813. [Abstract] [Full Text] [PDF]

				D. K. Kalra, X. Zhu, M. K. Ramchandani, G. Lawrie, M. J. Reardon, D. Lee-Jackson, W. L. Winters, N. Sivasubramanian, D. L. Mann, and W. A. Zoghbi Increased Myocardial Gene Expression of Tumor Necrosis Factor-{alpha} and Nitric Oxide Synthase-2: A Potential Mechanism for Depressed Myocardial Function in Hibernating Myocardium in Humans Circulation, April 2, 2002; 105(13): 1537 - 1540. [Abstract] [Full Text] [PDF]

				D. Kalra, N. Sivasubramanian, and D. L. Mann Angiotensin II Induces Tumor Necrosis Factor Biosynthesis in the Adult Mammalian Heart Through a Protein Kinase C-Dependent Pathway Circulation, May 7, 2002; 105(18): 2198 - 2205. [Abstract] [Full Text] [PDF]

				G. Baumgarten, P. Knuefermann, D. Kalra, F. Gao, G. E. Taffet, L. Michael, P. J. Blackshear, E. Carballo, N. Sivasubramanian, and D. L. Mann Load-Dependent and -Independent Regulation of Proinflammatory Cytokine and Cytokine Receptor Gene Expression in the Adult Mammalian Heart Circulation, May 7, 2002; 105(18): 2192 - 2197. [Abstract] [Full Text] [PDF]