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Central TNF inhibition results in attenuated neurohumoral excitation in heart failure: a role for superoxide and nitric oxide

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Abstract

This study examined the effect of central tumor necrosis factor-alpha (TNF) blockade on the imbalance between nitric oxide and superoxide production in the paraventricular nucleus (PVN) and ventrolateral medulla (VLM), key autonomic regulators, and their contribution to enhanced sympathetic drive in mice with congestive heart failure (CHF). We also used a TNF gene knockout (KO) mouse model to study the involvement of TNF in body fluid homeostasis and sympathoexcitation in CHF. After implantation of intracerebroventricular (ICV) cannulae, myocardial infarction (MI) was induced in wild-type (WT) and KO mice by coronary artery ligation. Osmotic mini-pumps were implanted into one set of WT + MI/Sham mice for continuous ICV infusion of Etanercept (ETN), a TNF receptor fusion protein, or vehicle (VEH). Gene expressions of neuronal nitric oxide synthase (NOS) and angiotensin receptor-type 2 were reduced, while those of inducible NOS, Nox2 homologs, superoxide, peroxynitrite and angiotensin receptor-type 1 were elevated in the brainstem and hypothalamus of MI + VEH. Plasma norepinephrine levels and the number of Fos-positive neurons were also increased in the PVN and VLM in MI + VEH. MI + ETN and KO + MI mice exhibited reduced oxidative stress, reduced sympathoexcitation and an improved cardiac function. These changes in WT + MI were associated with increased sodium and fluid retention. These results indicate that elevated TNF in these autonomic regulatory regions of the brain alter the production of superoxide and nitric oxide, contributing to fluid imbalance and sympathoexcitation in CHF.

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References

  1. Banks WA (2005) Blood–brain barrier transport of cytokines: a mechanism for neuropathology. Curr Pharm Des 11:973–984

    Article  CAS  PubMed  Google Scholar 

  2. Bozkurt B, Kribbs SB, Clubb FJ Jr, Michael LH, Didenko VV, Hornsby PJ, Seta Y, Oral H, Spinale FG, Mann DL (1998) Pathophysiologically relevant concentrations of tumor necrosis factor-alpha promote progressive left ventricular dysfunction and remodeling in rats. Circulation 97:1382–1391

    CAS  PubMed  Google Scholar 

  3. Campese VM, Shaohua Y, Huiquin Z (2005) Oxidative stress mediates angiotensin II-dependent stimulation of sympathetic nerve activity. Hypertension 46:533–539. doi:01.HYP.0000179088.57586.26

    Article  CAS  PubMed  Google Scholar 

  4. Campese VM, Ye S, Zhong H (2002) Downregulation of neuronal nitric oxide synthase and interleukin-1beta mediates angiotensin II-dependent stimulation of sympathetic nerve activity. Hypertension 39:519–524

    Article  CAS  PubMed  Google Scholar 

  5. Canton M, Skyschally A, Menabo R, Boengler K, Gres P, Schulz R, Haude M, Erbel R, Di Lisa F, Heusch G (2006) Oxidative modification of tropomyosin and myocardial dysfunction following coronary microembolization. Eur Heart J 27:875–881. doi:ehi751

    Article  CAS  PubMed  Google Scholar 

  6. Chan JY, Wang LL, Lee HY, Chan SH (2002) Augmented upregulation by c-fos of angiotensin subtype 1 receptor in nucleus tractus solitarii of spontaneously hypertensive rats. Hypertension 40:335–341

    Article  CAS  PubMed  Google Scholar 

  7. Chappell D, Hofmann-Kiefer K, Jacob M, Rehm M, Briegel J, Welsch U, Conzen P, Becker BF (2009) TNF-alpha induced shedding of the endothelial glycocalyx is prevented by hydrocortisone and antithrombin. Basic Res Cardiol 104:78–89. doi:10.1007/s00395-008-0749-5

    Article  CAS  PubMed  Google Scholar 

  8. Chorianopoulos E, Heger T, Lutz M, Frank D, Bea F, Katus HA, Frey N (2010) FGF-inducible 14 kDa protein (Fn14) is regulated via the RhoA/ROCK kinase pathway in cardiomyocytes and mediates nuclear factor-kappaB activation by TWEAK. Basic Res Cardiol 105:301–313. doi:10.1007/s00395-009-0046-y

    Article  CAS  PubMed  Google Scholar 

  9. Dikalov SI, Dikalova AE, Mason RP (2002) Noninvasive diagnostic tool for inflammation-induced oxidative stress using electron spin resonance spectroscopy and an extracellular cyclic hydroxylamine. Arch Biochem Biophys 402:218–226. doi:10.1016/S0003-9861(02)00064-4

    Article  CAS  PubMed  Google Scholar 

  10. Fildes JE, Shaw SM, Yonan N, Williams SG (2009) The immune system and chronic heart failure: is the heart in control? J Am Coll Cardiol 53:1013–1020. S0735-1097(09)00024-2 [pii]

    Google Scholar 

  11. Fleegal-DeMotta MA, Doghu S, Banks WA (2009) Angiotensin II modulates BBB permeability via activation of the AT(1) receptor in brain endothelial cells. J Cereb Blood Flow Metab 29:640–647. doi:10.1038/jcbfm.2008.158

  12. Francis J, Weiss RM, Wei SG, Johnson AK, Felder RB (2001) Progression of heart failure after myocardial infarction in the rat. Am J Physiol Regul Integr Comp Physiol 281:R1734–R1745

    CAS  PubMed  Google Scholar 

  13. Galiano M, Liu ZQ, Kalla R, Bohatschek M, Koppius A, Gschwendtner A, Xu S, Werner A, Kloss CU, Jones LL, Bluethmann H, Raivich G (2001) Interleukin-6 (IL6) and cellular response to facial nerve injury: effects on lymphocyte recruitment, early microglial activation and axonal outgrowth in IL6-deficient mice. Eur J Neurosci 14:327–341. ejn1647 [pii]

    Google Scholar 

  14. Gao L, Wang W, Li YL, Schultz HD, Liu D, Cornish KG, Zucker IH (2005) Sympathoexcitation by central ANG II: roles for AT1 receptor upregulation and NAD(P)H oxidase in RVLM. Am J Physiol Heart Circ Physiol 288:H2271–2279. 00949.2004 [pii]

    Google Scholar 

  15. Gloor SM, Wachtel M, Bolliger MF, Ishihara H, Landmann R, Frei K (2001) Molecular and cellular permeability control at the blood-brain barrier. Brain Res Brain Res Rev 36:258–264. S0165017301001023 [pii]

    Google Scholar 

  16. Guggilam A, Haque M, Kerut EK, McIlwain E, Lucchesi P, Seghal I, Francis J (2007) TNF-alpha blockade decreases oxidative stress in the paraventricular nucleus and attenuates sympathoexcitation in heart failure rats. Am J Physiol Heart Circ Physiol 293:H599–H609. 00286.2007 [pii]

    Google Scholar 

  17. Guggilam A, Patel KP, Haque M, Ebenezer PJ, Kapusta DR, Francis J (2008) Cytokine blockade attenuates sympathoexcitation in heart failure: cross-talk between nNOS, AT-1R and cytokines in the hypothalamic paraventricular nucleus. Eur J Heart Fail 10:625–634. S1388-9842(08)00196-7 [pii]

    Google Scholar 

  18. Han Y, Shi Z, Zhang F, Yu Y, Zhong MK, Gao XY, Wang W, Zhu GQ (2007) Reactive oxygen species in the paraventricular nucleus mediate the cardiac sympathetic afferent reflex in chronic heart failure rats. Eur J Heart Fail 9:967–973. S1388-9842(07)00267-X [pii]

    Google Scholar 

  19. Hill JA, Karimi M, Kutschke W, Davisson RL, Zimmerman K, Wang Z, Kerber RE, Weiss RM (2000) Cardiac hypertrophy is not a required compensatory response to short-term pressure overload. Circulation 101:2863–2869

    CAS  PubMed  Google Scholar 

  20. Hu K, Bahner U, Gaudron P, Palkovits M, Ring M, Fehle A, Kruse B, Ertl G (2001) Chronic effects of ACE-inhibition (quinapril) and angiotensin-II-type-1 receptor blockade (losartan) on atrial natriuretic peptide in brain nuclei of rats with experimental myocardial infarction. Basic Res Cardiol 96:258–266

    Article  CAS  PubMed  Google Scholar 

  21. Huang CH, Vallejo JG, Kollias G, Mann DL (2009) Role of the innate immune system in acute viral myocarditis. Basic Res Cardiol 104:228–237. doi:10.1007/s00395-008-0765-5

    Article  CAS  PubMed  Google Scholar 

  22. Johnson AK, Thunhorst RL (1997) The neuroendocrinology of thirst and salt appetite: visceral sensory signals and mechanisms of central integration. Front Neuroendocrinol 18:292–353. S0091-3022(97)90153-9 [pii]

    Google Scholar 

  23. Khaleduzzaman M, Francis J, Corbin ME, McIlwain E, Boudreaux M, Du M, Morgan TW, Peterson KE (2007) Infection of cardiomyocytes and induction of left ventricle dysfunction by neurovirulent polytropic murine retrovirus. J Virol 81:12307–12315. JVI.01002-07 [pii]

    Google Scholar 

  24. Kleinbongard P, Heusch G, Schulz R (2010) TNF alpha in atherosclerosis, myocardial ischemia/reperfusion and heart failure. Pharmacol Ther 127:295–314. S0163-7258(10)00114-2 [pii]

    Google Scholar 

  25. Krown KA, Page MT, Nguyen C, Zechner D, Gutierrez V, Comstock KL, Glembotski CC, Quintana PJ, Sabbadini RA (1996) Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death. J Clin Invest 98:2854–2865. doi:10.1172/JCI119114

    Article  CAS  PubMed  Google Scholar 

  26. Lacerda L, McCarthy J, Mungly SF, Lynn EG, Sack MN, Opie LH, Lecour S (2010) TNFalpha protects cardiac mitochondria independently of its cell surface receptors. Basic Res Cardiol 105:751–762. doi:10.1007/s00395-010-0113-4

    Article  CAS  PubMed  Google Scholar 

  27. Li S, Zhong S, Zeng K, Luo Y, Zhang F, Sun X, Chen L (2010) Blockade of NF-kappaB by pyrrolidine dithiocarbamate attenuates myocardial inflammatory response and ventricular dysfunction following coronary microembolization induced by homologous microthrombi in rats. Basic Res Cardiol 105:139–150. doi:10.1007/s00395-009-0067-6

    Article  CAS  PubMed  Google Scholar 

  28. Li YF, Wang W, Mayhan WG, Patel KP (2006) Angiotensin-mediated increase in renal sympathetic nerve discharge within the PVN: role of nitric oxide. Am J Physiol Regul Integr Comp Physiol 290:R1035–1043. 00338.2004 [pii]

    Google Scholar 

  29. Lindley TE, Doobay MF, Sharma RV, Davisson RL (2004) Superoxide is involved in the central nervous system activation and sympathoexcitation of myocardial infarction-induced heart failure. Circ Res 94:402–409. doi:10.1161/01.RES.0000112964.40701.93

    Article  CAS  PubMed  Google Scholar 

  30. Liu JL, Zucker IH (1999) Regulation of sympathetic nerve activity in heart failure: a role for nitric oxide and angiotensin II. Circ Res 84:417–423

    CAS  PubMed  Google Scholar 

  31. Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS, Djian J, Drexler H, Feldman A, Kober L, Krum H, Liu P, Nieminen M, Tavazzi L, van Veldhuisen DJ, Waldenstrom A, Warren M, Westheim A, Zannad F, Fleming T (2004) Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 109:1594–1602. doi:10.1161/01.CIR.0000124490.27666.B2

    Article  CAS  PubMed  Google Scholar 

  32. Mayorov DN, Head GA, De Matteo R (2004) Tempol attenuates excitatory actions of angiotensin II in the rostral ventrolateral medulla during emotional stress. Hypertension 44:101–106. doi:10.1161/01.HYP.0000131290.12255.04

    Article  CAS  PubMed  Google Scholar 

  33. McCann SM, Kimura M, Karanth S, Yu WH, Mastronardi CA, Rettori V (2000) The mechanism of action of cytokines to control the release of hypothalamic and pituitary hormones in infection. Ann N Y Acad Sci 917:4–18

    Article  CAS  PubMed  Google Scholar 

  34. Raivich G, Moreno-Flores MT, Muller JC, Kreutzberg GW (1994) Regulation of microglial proliferation: colony-stimulating factors and their receptors. Neuropathol Appl Neurobiol 20:209–211

    CAS  PubMed  Google Scholar 

  35. Sakuma I, Togashi H, Yoshioka M, Saito H, Yanagida M, Tamura M, Kobayashi T, Yasuda H, Gross SS, Levi R (1992) NG-methyl-l-arginine, an inhibitor of l-arginine-derived nitric oxide synthesis, stimulates renal sympathetic nerve activity in vivo. A role for nitric oxide in the central regulation of sympathetic tone? Circ Res 70:607–611

    CAS  PubMed  Google Scholar 

  36. Sasaki S, Dampney RA (1990) Tonic cardiovascular effects of angiotensin II in the ventrolateral medulla. Hypertension 15:274–283

    CAS  PubMed  Google Scholar 

  37. Schiller NB, Acquatella H, Ports TA, Drew D, Goerke J, Ringertz H, Silverman NH, Brundage B, Botvinick EH, Boswell R, Carlsson E, Parmley WW (1979) Left ventricular volume from paired biplane two-dimensional echocardiography. Circulation 60:547–555

    CAS  PubMed  Google Scholar 

  38. Sheng JG, Mrak RE, Griffin WS (1998) Enlarged and phagocytic, but not primed, interleukin-1 alpha-immunoreactive microglia increase with age in normal human brain. Acta Neuropathol 95:229–234

    Article  CAS  PubMed  Google Scholar 

  39. Shi P, Diez-Freire C, Jun JY, Qi Y, Katovich MJ, Li Q, Sriramula S, Francis J, Sumners C, Raizada MK Brain microglial cytokines in neurogenic hypertension. Hypertension 56:297–303. HYPERTENSIONAHA.110.150409 [pii]

  40. Thielmann M, Dorge H, Martin C, Belosjorow S, Schwanke U, van De Sand A, Konietzka I, Buchert A, Kruger A, Schulz R, Heusch G (2002) Myocardial dysfunction with coronary microembolization: signal transduction through a sequence of nitric oxide, tumor necrosis factor-alpha, and sphingosine. Circ Res 90:807–813

    Article  CAS  PubMed  Google Scholar 

  41. Torre-Amione G, Kapadia S, Benedict C, Oral H, Young J, Mann D (1996) Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 27:1201–1206

    Article  CAS  PubMed  Google Scholar 

  42. Tsutamoto T, Hisanaga T, Wada A, Maeda K, Ohnishi M, Fukai D, Mabuchi N, Sawaki M, Kinoshita M (1998) Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure. J Am Coll Cardiol 31:391–398

    Article  CAS  PubMed  Google Scholar 

  43. Unger T, Badoer E, Ganten D, Lang RE, Rettig R (1988) Brain angiotensin: pathways and pharmacology. Circulation 77:I40–I54

    CAS  PubMed  Google Scholar 

  44. Vahid-Ansari F, Leenen FH (1998) Pattern of neuronal activation in rats with CHF after myocardial infarction. Am J Physiol 275:H2140–H2146

    CAS  PubMed  Google Scholar 

  45. Veerasingham SJ, Leenen FH (1997) Excitotoxic lesions of the ventral anteroventral third ventricle and pressor responses to central sodium, ouabain and angiotensin II. Brain Res 749:157–160. S0006-8993(96)01381-9 [pii]

    Google Scholar 

  46. Wei SG, Zhang ZH, Yu Y, Felder RB (2009) Systemically administered tempol reduces neuronal activity in paraventricular nucleus of hypothalamus and rostral ventrolateral medulla in rats. J Hypertens 27:543–550

    Google Scholar 

  47. Yu Y, Zhang ZH, Wei SG, Serrats J, Weiss RM, Felder RB (2010) Brain perivascular macrophages and the sympathetic response to inflammation in rats after myocardial infarction. Hypertension 55:652–659. doi:10.1161/HYPERTENSIONAHA.109.142836

    Google Scholar 

  48. Zanzinger J (2002) Mechanisms of action of nitric oxide in the brain stem: role of oxidative stress. Auton Neurosci 98:24–27. S1566-0702(02)00025-5 [pii]

    Google Scholar 

  49. Zanzinger J, Czachurski J, Seller H (1995) Inhibition of basal and reflex-mediated sympathetic activity in the RVLM by nitric oxide. Am J Physiol 268:R958–R962

    CAS  PubMed  Google Scholar 

  50. Zhang C, Wu J, Xu X, Potter BJ, Gao X (2010) Direct relationship between levels of TNF-alpha expression and endothelial dysfunction in reperfusion injury. Basic Res Cardiol 105:453–464. doi:10.1007/s00395-010-0083-6

    Article  CAS  PubMed  Google Scholar 

  51. Zhang M, Mao Y, Ramirez SH, Tuma RF, Chabrashvili T (2010) Angiotensin II induced cerebral microvascular inflammation and increased blood-brain barrier permeability via oxidative stress. Neuroscience 171:852–858. S0306-4522(10)01277-7 [pii]

    Google Scholar 

  52. Zimmerman MC, Lazartigues E, Lang JA, Sinnayah P, Ahmad IM, Spitz DR, Davisson RL (2002) Superoxide mediates the actions of angiotensin II in the central nervous system. Circ Res 91:1038–1045

    Article  CAS  PubMed  Google Scholar 

  53. Zimmerman MC, Lazartigues E, Sharma RV, Davisson RL (2004) Hypertension caused by angiotensin II infusion involves increased superoxide production in the central nervous system. Circ Res 95:210–216. doi:10.1161/01.RES.0000135483.12297.e4

    Article  CAS  PubMed  Google Scholar 

  54. Zucker IH, Pliquett RU (2002) Novel mechanisms of sympatho-excitation in chronic heart failure. Heart Fail Monit 3:2–7

    CAS  PubMed  Google Scholar 

  55. Zucker IH, Schultz HD, Li YF, Wang Y, Wang W, Patel KP (2004) The origin of sympathetic outflow in heart failure: the roles of angiotensin II and nitric oxide. Prog Biophys Mol Biol 84:217–232. doi:10.1016/j.pbiomolbio.2003.11.010

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by National Heart, Lung, and Blood Institute Grant (1RO1 HL-080544-01 to J.F.). The authors acknowledge the expert technical assistance of Elizabeth McIlwain, Philip J. Ebenezer, Michael Broussard and Sherry Ring.

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None declared.

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Authors and Affiliations

  1. Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, 1909 Skip Bertman Drive, Baton Rouge, LA, 70803, USA

    Anuradha Guggilam, Jeffrey P. Cardinale, Nithya Mariappan, Srinivas Sriramula, Masudul Haque & Joseph Francis

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  1. Anuradha Guggilam
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  2. Jeffrey P. Cardinale
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  3. Nithya Mariappan
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  4. Srinivas Sriramula
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Correspondence to Joseph Francis.

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A. Guggilam and J. P. Cardinale have contributed equally to this work.

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Guggilam, A., Cardinale, J.P., Mariappan, N. et al. Central TNF inhibition results in attenuated neurohumoral excitation in heart failure: a role for superoxide and nitric oxide. Basic Res Cardiol 106, 273–286 (2011). https://doi.org/10.1007/s00395-010-0146-8

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