© 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
This article has been cited by other articles:
 |
|
 |
|
  H. E. Tawfik, J. Cena, R. Schulz, and S. Kaufman Role of oxidative stress in multiparity-induced endothelial dysfunction Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1736 - H1742. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Mizukami, K. Ono, C.-K. Du, T. Aki, N. Hatano, Y. Okamoto, Y. Ikeda, H. Ito, K. Hamano, and S. Morimoto Identification and physiological activity of survival factor released from cardiomyocytes during ischaemia and reperfusion Cardiovasc Res, September 1, 2008; 79(4): 589 - 599. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Frei, Y. Guo, D. W. Jones, K. A. Pritchard Jr, K. A. Fagan, N. Hogg, and N. J. Wandersee Vascular dysfunction in a murine model of severe hemolysis Blood, July 15, 2008; 112(2): 398 - 405. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Song, Z. Xie, Y. Wu, J. Xu, Y. Dong, and M.-H. Zou Protein Kinase C{zeta}-dependent LKB1 Serine 428 Phosphorylation Increases LKB1 Nucleus Export and Apoptosis in Endothelial Cells J. Biol. Chem., May 2, 2008; 283(18): 12446 - 12455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kaiserova, X.-L. Tang, S. Srivastava, and A. Bhatnagar Role of Nitric Oxide in Regulating Aldose Reductase Activation in the Ischemic Heart J. Biol. Chem., April 4, 2008; 283(14): 9101 - 9112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D.-Z. Hsu, S.-P. Chien, Y.-H. Li, Y.-C. Chuang, Y.-C. Chang, and M.-Y. Liu Sesame Oil Attenuates Hepatic Lipid Peroxidation by Inhibiting Nitric Oxide and Superoxide Anion Generation in Septic Rats JPEN J Parenter Enteral Nutr, March 1, 2008; 32(2): 154 - 159. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Kohr, H. Wang, D. G. Wheeler, M. Velayutham, J. L. Zweier, and M. T. Ziolo Targeting of phospholamban by peroxynitrite decreases {beta}-adrenergic stimulation in cardiomyocytes Cardiovasc Res, January 15, 2008; 77(2): 353 - 361. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Beausejour, V. Houde, K. Bibeau, R. Gaudet, J. St-Louis, and M. Brochu Renal and cardiac oxidative/nitrosative stress in salt-loaded pregnant rat Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1657 - R1665. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Li, X. Jiao, L. Tao, H. Liu, Y. Cao, B. L. Lopez, T. A. Christopher, and X. L. Ma Tumor necrosis factor-{alpha} in mechanic trauma plasma mediates cardiomyocyte apoptosis Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1847 - H1852. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.W. Merx and C. Weber Sepsis and the Heart Circulation, August 14, 2007; 116(7): 793 - 802. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Guellich, T. Damy, Y. Lecarpentier, M. Conti, V. Claes, J.-L. Samuel, J. Quillard, J.-L. Hebert, T. Pineau, and C. Coirault Role of oxidative stress in cardiac dysfunction of PPAR{alpha}-/- mice Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H93 - H102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Schulz and M. A. M. Ali PPAR{alpha}: essential component to prevent myocardial oxidative stress? Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H11 - H12. [Full Text] [PDF]
|
|
|
|
|
|
M. Fernandez-Velasco, G. Ruiz-Hurtado, O. Hurtado, M. A. Moro, and C. Delgado TNF-{alpha} downregulates transient outward potassium current in rat ventricular myocytes through iNOS overexpression and oxidant species generation Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H238 - H245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kajiya, M. Hirota, Y. Inai, T. Kiyooka, T. Morimoto, T. Iwasaki, K. Endo, S. Mohri, J. Shimizu, T. Yada, et al. Impaired NO-mediated vasodilation with increased superoxide but robust EDHF function in right ventricular arterial microvessels of pulmonary hypertensive rats Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2737 - H2744. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Peluffo L-Arginine currents in rat cardiac ventricular myocytes J. Physiol., May 1, 2007; 580(3): 925 - 936. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Tao, E. Gao, X. Jiao, Y. Yuan, S. Li, T. A. Christopher, B. L. Lopez, W. Koch, L. Chan, B. J. Goldstein, et al. Adiponectin Cardioprotection After Myocardial Ischemia/Reperfusion Involves the Reduction of Oxidative/Nitrative Stress Circulation, March 20, 2007; 115(11): 1408 - 1416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Niu, A. Azfer, L. M. Rogers, X. Wang, and P. E. Kolattukudy Cardioprotective effects of cerium oxide nanoparticles in a transgenic murine model of cardiomyopathy Cardiovasc Res, February 1, 2007; 73(3): 549 - 559. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pacher, J. S. Beckman, and L. Liaudet Nitric Oxide and Peroxynitrite in Health and Disease Physiol Rev, January 1, 2007; 87(1): 315 - 424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pacher, A. Nivorozhkin, and C. Szabo Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol. Rev., March 1, 2006; 58(1): 87 - 114. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Z. Zhu, C. L. Chong, S. C. Chuah, S. H. Huang, H. S. Nai, H. T. Tong, M. Whiteman, and P. K. Moore Cardioprotective effects of nitroparacetamol and paracetamol in acute phase of myocardial infarction in experimental rats Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H517 - H524. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-H. Liu, O. A. Carretero, O. H. Cingolani, T.-D. Liao, Y. Sun, J. Xu, L. Y. Li, P. J. Pagano, J. J. Yang, and X.-P. Yang Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2616 - H2623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Sun, O. A. Carretero, J. Xu, N.-E. Rhaleb, F. Wang, C. Lin, J. J. Yang, P. J. Pagano, and X.-P. Yang Lack of Inducible NO Synthase Reduces Oxidative Stress and Enhances Cardiac Response to Isoproterenol in Mice With Deoxycorticosterone Acetate-Salt Hypertension Hypertension, December 1, 2005; 46(6): 1355 - 1361. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. C. Mehra, V. S. Ramgolam, and J. R. Bender Cytokines and cardiovascular disease J. Leukoc. Biol., October 1, 2005; 78(4): 805 - 818. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. Masri, S. A. A. Comhair, T. Koeck, W. Xu, A. Janocha, S. Ghosh, R. A. Dweik, J. Golish, M. Kinter, D. J. Stuehr, et al. Abnormalities in Nitric Oxide and Its Derivatives in Lung Cancer Am. J. Respir. Crit. Care Med., September 1, 2005; 172(5): 597 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Paolocci Peroxynitrite like Pan? Cardiovasc Res, August 1, 2005; 67(2): 176 - 178. [Full Text] [PDF]
|
|
|
|
|
|
A. Borbely, A. Toth, I. Edes, L. Virag, J. G. Papp, A. Varro, W. J. Paulus, J. van der Velden, G. J.M. Stienen, and Z. Papp Peroxynitrite-induced {alpha}-actinin nitration and contractile alterations in isolated human myocardial cells Cardiovasc Res, August 1, 2005; 67(2): 225 - 233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-W. Yu, M.-Y. G Liu, R. H Kennedy, and S. J Liu Both cGMP and peroxynitrite mediate chronic interleukin-6-induced negative inotropy in adult rat ventricular myocytes J. Physiol., July 15, 2005; 566(2): 341 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Pieper, V. Nilakantan, M. Chen, J. Zhou, A. K. Khanna, J. D. Henderson Jr., C. P. Johnson, A. M. Roza, and C. Szabo Protective Mechanisms of a Metalloporphyrinic Peroxynitrite Decomposition Catalyst, WW85, in Rat Cardiac Transplants J. Pharmacol. Exp. Ther., July 1, 2005; 314(1): 53 - 60. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Tao, H.-R. Liu, F. Gao, Y. Qu, T. A. Christopher, B. L. Lopez, and X. L. Ma Mechanical traumatic injury without circulatory shock causes cardiomyocyte apoptosis: role of reactive nitrogen and reactive oxygen species Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2811 - H2818. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Sharony, I. Frolkis, D. Froylich, S. M. Wildhirt, I. Shapira, B. Reichart, N. Nesher, and G. Uretzky Pharmacological preconditioning with monophosphoryl lipid A improves post ischemic diastolic function and modifies TNF-alpha synthesis Eur. J. Cardiothorac. Surg., March 1, 2005; 27(3): 501 - 507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Xu, M. Gen, L. Lu, J. Fox, S. O. Weiss, R. D. Brown, D. Perlov, H. Ahmad, P. Zhu, C. Greyson, et al. PPAR-{gamma} activation fails to provide myocardial protection in ischemia and reperfusion in pigs Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1314 - H1323. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. C. Colombo, J. E. Banchs, S. Celaj, A. Talreja, J. Lachmann, S. Malla, N. B. DuBois, A. W. Ashton, F. Latif, U. P. Jorde, et al. Endothelial Cell Activation in Patients With Decompensated Heart Failure Circulation, January 4, 2005; 111(1): 58 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. R. Madamanchi, A. Vendrov, and M. S. Runge Oxidative Stress and Vascular Disease Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 29 - 38. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Chen, M. Hou, Y. Li, J. H. Traverse, P. Zhang, D. Salvemini, T. Fukai, and R. J. Bache Increased superoxide production causes coronary endothelial dysfunction and depressed oxygen consumption in the failing heart Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H133 - H141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Jones, J. J. M. Greer, P. D. Ware, J. Yang, K. Walsh, and D. J. Lefer Deficiency of iNOS does not attenuate severe congestive heart failure in mice Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H365 - H370. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. D. Prabhu Cytokine-Induced Modulation of Cardiac Function Circ. Res., December 10, 2004; 95(12): 1140 - 1153. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Kowluru and S. Odenbach Role of Interleukin-1{beta} in the Development of Retinopathy in Rats: Effect of Antioxidants Invest. Ophthalmol. Vis. Sci., November 1, 2004; 45(11): 4161 - 4166. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Cheng, X. S. Cheng, K.-H. Kuo, and C. C.Y. Pang Inhibition of iNOS augments cardiovascular action of noradrenaline in streptozotocin-induced diabetes Cardiovasc Res, November 1, 2004; 64(2): 298 - 307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nian, P. Lee, N. Khaper, and P. Liu Inflammatory Cytokines and Postmyocardial Infarction Remodeling Circ. Res., June 25, 2004; 94(12): 1543 - 1553. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Lancel, S. Tissier, S. Mordon, X. Marechal, F. Depontieu, A. Scherpereel, C. Chopin, and R. Neviere Peroxynitrite decomposition catalysts prevent myocardial dysfunction and inflammation in endotoxemic rats J. Am. Coll. Cardiol., June 16, 2004; 43(12): 2348 - 2358. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Saraswathi, G. Wu, M. Toborek, and B. Hennig Linoleic acid-induced endothelial activation: role of calcium and peroxynitrite signaling J. Lipid Res., May 1, 2004; 45(5): 794 - 804. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Nadruz Jr, V. J. Lagosta, H. Moreno Jr, O. R. Coelho, and K. G. Franchini Simvastatin Prevents Load-Induced Protein Tyrosine Nitration in Overloaded Hearts Hypertension, May 1, 2004; 43(5): 1060 - 1066. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Brunner and G. Wolkart Peroxynitrite-induced cardiac depression: role of myofilament desensitization and cGMP pathway Cardiovasc Res, November 1, 2003; 60(2): 355 - 364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. White, D. L. Carlson, M. Thompson, D. L. Maass, B. Sanders, B. Giroir, and J. W. Horton Molecular and pharmacological approaches to inhibiting nitric oxide after burn trauma Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1616 - H1625. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Wunderlich, U. Flogel, A. Godecke, J. Heger, and J. Schrader Acute Inhibition of Myoglobin Impairs Contractility and Energy State of iNOS-Overexpressing Hearts Circ. Res., June 27, 2003; 92(12): 1352 - 1358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Warnholtz and T. Munzel The failing human heart: Another battlefield for the NAD(P)H oxidase? J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2172 - 2174. [Full Text] [PDF]
|
|
|
|
|
|
A. Onody, C. Csonka, Z. Giricz, and P. Ferdinandy Hyperlipidemia induced by a cholesterol-rich diet leads to enhanced peroxynitrite formation in rat hearts Cardiovasc Res, June 1, 2003; 58(3): 663 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Rugale, S. Delbosc, J.-P. Cristol, A. Mimran, and B. Jover Sodium restriction prevents cardiac hypertrophy and oxidative stress in angiotensin II hypertension Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1744 - H1750. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Pacher, L. Liaudet, P. Bai, J. G. Mabley, P. M. Kaminski, L. Virag, A. Deb, E. Szabo, Z. Ungvari, M. S. Wolin, et al. Potent Metalloporphyrin Peroxynitrite Decomposition Catalyst Protects Against the Development of Doxorubicin-Induced Cardiac Dysfunction Circulation, February 18, 2003; 107(6): 896 - 904. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Qun Gao, G. Sawicki, W. L Suarez-Pinzon, T. Csont, M. Wozniak, P. Ferdinandy, and R. Schulz Matrix metalloproteinase-2 mediates cytokine-induced myocardial contractile dysfunction Cardiovasc Res, February 1, 2003; 57(2): 426 - 433. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Mehlhorn, A. Krahwinkel, H. J. Geissler, K. LaRosee, U. M. Fischer, O. Klass, M. Suedkamp, K. Hekmat, P. Tossios, and W. Bloch Nitrotyrosine and 8-isoprostane formation indicate free radical-mediated injury in hearts of patients subjected to cardioplegia J. Thorac. Cardiovasc. Surg., January 1, 2003; 125(1): 178 - 183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Kaye, M. M. Parnell, and B. A. Ahlers Reduced Myocardial and Systemic L-Arginine Uptake in Heart Failure Circ. Res., December 13, 2002; 91(12): 1198 - 1203. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. V. Turko and F. Murad Protein Nitration in Cardiovascular Diseases Pharmacol. Rev., December 1, 2002; 54(4): 619 - 634. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Loubani and M. Galinanes Long-term administration of nicorandil abolishes ischemic and pharmacologic preconditioning of the human myocardium: Role of mitochondrial adenosine triphosphate-dependent potassium channels J. Thorac. Cardiovasc. Surg., October 1, 2002; 124(4): 750 - 757. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Bianchi, H. Wakiyama, R. Faro, T. Khan, J. D. McCully, S. Levitsky, C. Szabo, and F. W. Sellke A novel peroxynitrite decomposer catalyst (FP-15) reduces myocardial infarct size in an in vivo peroxynitrite decomposer and acute ischemia-reperfusion in pigs Ann. Thorac. Surg., October 1, 2002; 74(4): 1201 - 1207. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. D. Thomas, M. G. Espey, M. P. Vitek, K. M. Miranda, and D. A. Wink Protein nitration is mediated by heme and free metals through Fenton-type chemistry: An alternative to the NO/O2- reaction PNAS, October 1, 2002; 99(20): 12691 - 12696. [Abstract] [Full Text] [PDF]
|