© 2000 American Heart Association, Inc.
Integrative Physiology |
Peroxynitrite Is a Major Contributor to Cytokine-Induced Myocardial Contractile Failure
From the Cardiovascular Research Group, Departments of Pediatrics (R.S.), Pharmacology (P.F., H.D., I.A., R.S.), and Biochemistry (R.A.R.), Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada, and Department of Biochemistry (P.F., I.A.), University of Szeged, Hungary.
Correspondence to Dr Richard Schulz, Cardiovascular Research Group, 4-62 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. E-mail richard.schulz{at}ualberta.ca
Abstract—Proinflammatory
cytokines depress myocardial contractile function by enhancing
the expression of inducible NO synthase (iNOS), yet the mechanism of
iNOS-mediated myocardial injury is not clear. As the reaction of NO
with superoxide to form peroxynitrite markedly enhances the toxicity of
NO, we hypothesized that peroxynitrite itself is responsible for
cytokine-induced cardiac depression. Isolated working rat
hearts were perfused for 120 minutes with buffer containing
interleukin-1ß, interferon-
, and tumor necrosis factor-
.
Cardiac mechanical function and myocardial iNOS, xanthine
oxidoreductase (XOR), and NAD(P)H oxidase activities (sources of
superoxide) were measured during the perfusion. Cytokines
induced a marked decline in myocardial contractile function accompanied
by enhanced activity of myocardial XOR, NADH oxidase, and iNOS. Cardiac
NO content, myocardial superoxide production, and
perfusate nitrotyrosine and dityrosine levels, markers of
peroxynitrite, were increased in cytokine-treated hearts. The
peroxynitrite decomposition catalyst FeTPPS
(5,10,15,20-tetrakis-[4-sulfonatophenyl]-porphyrinato-iron[III]),
the NO synthase inhibitor
NG-nitro-L-arginine, and the
superoxide scavenger tiron each inhibited the decline in myocardial
function and decreased perfusate nitrotyrosine levels.
Proinflammatory cytokines stimulate the concerted enhancement
in superoxide and NO-generating activities in the heart, thereby
enhancing peroxynitrite generation, which causes myocardial
contractile failure.
Key Words: cytokines • nitric oxide synthase • xanthine • oxidoreductases • NADPH oxidase
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H. Chen, D. Li, T. Saldeen, and J. L. Mehta TGF-{beta}1 modulates NOS expression and phosphorylation of Akt/PKB in rat myocytes exposed to hypoxia-reoxygenation Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1035 - H1039. [Abstract] [Full Text] [PDF]
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Q. Feng, X. Lu, D. L. Jones, J. Shen, and J. M. O. Arnold Increased Inducible Nitric Oxide Synthase Expression Contributes to Myocardial Dysfunction and Higher Mortality After Myocardial Infarction in Mice Circulation, August 7, 2001; 104(6): 700 - 704. [Abstract] [Full Text] [PDF]
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D. Pevni, I. Frolkis, A. Iaina, Y. Wollman, T. Chernichovski, I. Shapira, G. Uretzky, and R. Mohr Protamine cardiotoxicity and nitric oxide Eur. J. Cardiothorac. Surg., July 1, 2001; 20(1): 147 - 152. [Abstract] [Full Text] [PDF]
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G. Merrill, P. McConnell, K. Vandyke, and S. Powell Coronary and myocardial effects of acetaminophen: protection during ischemia-reperfusion Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2631 - H2638. [Abstract] [Full Text] [PDF]
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 M.-S. Zhou, A. Adam, and L. Raij Review: Interaction among angiotensin II, nitric oxide and oxidative stress Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S59 - S63. [PDF]
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P. Ferdinandy and R. Schulz Peroxynitrite: Toxic or Protective in the Heart? Circ. Res., February 2, 2001; 88 (2): e12 - e13. [Full Text] [PDF]
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J. Vinten-Johansen Physiological Effects of Peroxynitrite : Potential Products of the Environment Circ. Res., August 4, 2000; 87(3): 170 - 172. [Full Text] [PDF]
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 A. U. Khan, R. L. Delude, Y. Y. Han, P. L. Sappington, X. Han, J. A. Carcillo, and M. P. Fink Liposomal NAD+ prevents diminished O2 consumption by immunostimulated Caco-2 cells Am J Physiol Lung Cell Mol Physiol, May 1, 2002; 282(5): L1082 - L1091. [Abstract] [Full Text] [PDF]
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W. F. Saavedra, N. Paolocci, M. E. St. John, M. W. Skaf, G. C. Stewart, J.-S. Xie, R. W. Harrison, J. Zeichner, D. Mudrick, E. Marban, et al. Imbalance Between Xanthine Oxidase and Nitric Oxide Synthase Signaling Pathways Underlies Mechanoenergetic Uncoupling in the Failing Heart Circ. Res., February 22, 2002; 90(3): 297 - 304. [Abstract] [Full Text] [PDF]
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