Basic Research in Cardiology

, Volume 106, Issue 6, pp 1193–1205 | Cite as

Tumor necrosis factor receptor 2 signaling limits β-adrenergic receptor-mediated cardiac hypertrophy in vivo

  • Jason B. Garlie
  • Tariq Hamid
  • Yan Gu
  • Mohamed Ameen Ismahil
  • Bysani Chandrasekar
  • Sumanth D. Prabhu
Original Contribution

Abstract

The in vivo role of TNF signaling in the genesis of β-adrenergic receptor (β-AR)-mediated cardiac hypertrophy is unknown. Wild-type (WT), TNF receptor 1 (TNFR1)-/- and TNFR2-/- mice were given isoproterenol (ISO, 12.5 μg/kg/h) or saline (SAL) for 1 or 7 days. In WT mice, 7 days of ISO yielded chamber/myocyte hypertrophy and hyperdynamic function without hypertension or fibrosis. WT ISO hearts exhibited an early (1 day) pro-inflammatory response with significant (p < 0.05) activation of nuclear factor (NF)-κB and activator protein 1 (AP-1) and upregulation of TNF, interleukin (IL)-1β and IL-6, inducible nitric oxide synthase (iNOS) and monocyte chemotactic protein-1 (MCP-1), together with increased anti-inflammatory IL-10. This response diminished markedly by 7 days. As compared with WT ISO mice, TNFR1-/- ISO mice exhibited significantly (p < 0.05) less NF-κB and AP-1 activation, less IL-1β, TNF, iNOS and MCP-1 upregulation, but greater IL-10 at 1 day. However, there were no differences in hypertrophy or contractility at 7 days. In contrast, TNFR2-/- ISO mice exhibited augmented NF-κB and AP-1 activation, increased IL-1β and diminished IL-10 expression at 1 day, and significant exaggeration of hypertrophy and less contractile augmentation at 7 days. Moreover, TNFR2-/- mice exposed to tenfold higher ISO doses displayed significant mortality. TNF signaling contributes to β-AR-mediated cardiac remodeling in vivo in a receptor-specific manner. Unopposed TNFR1 activation is pro-inflammatory, pro-hypertrophic and promotes functional decline. However, co-activation of TNFR2 during β-AR stress is anti-inflammatory and counterbalances these deleterious effects. TNF modulatory strategies that maintain TNFR2 signaling may help prevent the detrimental long-term effects of β-AR stimulation in the heart.

Keywords

Tumor necrosis factor Beta-adrenergic receptor Cardiac hypertrophy Cytokines Nuclear factor kappa B 

Supplementary material

395_2011_196_MOESM1_ESM.pdf (320 kb)
Supplementary material 1 (PDF 320 kb)

References

  1. 1.
    Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3:745–756PubMedCrossRefGoogle Scholar
  2. 2.
    Antos CL, Frey N, Marx SO, Reiken S, Gaburjakova M, Richardson JA, Marks AR, Olson EN (2001) Dilated cardiomyopathy and sudden death resulting from constitutive activation of protein kinase A. Circ Res 89:997–1004PubMedCrossRefGoogle Scholar
  3. 3.
    Bristow MR (2000) Beta-adrenergic receptor blockade in chronic heart failure. Circulation 101:558–569PubMedGoogle Scholar
  4. 4.
    Burger A, Benicke M, Deten A, Zimmer HG (2001) Catecholamines stimulate interleukin-6 synthesis in rat cardiac fibroblasts. Am J Physiol Heart Circ Physiol 281:H14–H21PubMedGoogle Scholar
  5. 5.
    Chandrasekar B, Marelli-Berg FM, Tone M, Bysani S, Prabhu SD, Murray DR (2004) Beta-adrenergic stimulation induces interleukin-18 expression via β2-AR, PI3K, Akt, IKK, and NF- κB. Biochem Biophys Res Commun 319:304–311PubMedCrossRefGoogle Scholar
  6. 6.
    Deswal A, Petersen NJ, Feldman AM, Young JB, White BG, Mann DL (2001) Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation 103:2055–2059PubMedGoogle Scholar
  7. 7.
    Ding P, Huang J, Battiprolu PK, Hill JA, Kamm KE, Stull JT (2010) Cardiac myosin light chain kinase is necessary for myosin regulatory light chain phosphorylation and cardiac performance in vivo. J Biol Chem 285:40819–40829PubMedCrossRefGoogle Scholar
  8. 8.
    Engelhardt S, Hein L, Wiesmann F, Lohse MJ (1999) Progressive hypertrophy and heart failure in β1-adrenergic receptor transgenic mice. Proc Natl Acad Sci USA 96:7059–7064PubMedCrossRefGoogle Scholar
  9. 9.
    Freire G, Ocampo C, Ilbawi N, Griffin AJ, Gupta M (2007) Overt expression of AP-1 reduces α-myosin heavy chain expression and contributes to heart failure from chronic volume overload. J Mol Cell Cardiol 43:465–478PubMedCrossRefGoogle Scholar
  10. 10.
    Guggilam A, Cardinale JP, Mariappan N, Sriramula S, Haque M, Francis J (2011) Central TNF inhibition results in attenuated neurohumoral excitation in heart failure: a role for superoxide and nitric oxide. Basic Res Cardiol 106:273–286PubMedCrossRefGoogle Scholar
  11. 11.
    Hamid T, Gu Y, Ortines RV, Bhattacharya C, Wang G, Xuan YT, Prabhu SD (2009) Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: role of nuclear factor-κB and inflammatory activation. Circulation 119:1386–1397PubMedCrossRefGoogle Scholar
  12. 12.
    Hamid T, Guo SZ, Kingery JR, Xiang X, Dawn B, Prabhu SD (2011) Cardiomyocyte NF-κB p65 promotes adverse remodelling, apoptosis, and endoplasmic reticulum stress in heart failure. Cardiovasc Res 89:129–138PubMedCrossRefGoogle Scholar
  13. 13.
    Heusch P, Aker S, Boengler K, Deindl E, van de Sand A, Klein K, Rassaf T, Konietzka I, Sewell A, Menazza S, Canton M, Heusch G, Di Lisa F, Schulz R (2010) Increased inducible nitric oxide synthase and arginase II expression in heart failure: no net nitrite/nitrate production and protein S-nitrosylation. Am J Physiol Heart Circ Physiol 299:H446–H453PubMedCrossRefGoogle Scholar
  14. 14.
    Honsho S, Nishikawa S, Amano K, Zen K, Adachi Y, Kishita E, Matsui A, Katsume A, Yamaguchi S, Nishikawa K, Isoda K, Riches DW, Matoba S, Okigaki M, Matsubara H (2009) Pressure-mediated hypertrophy and mechanical stretch induces IL-1 release and subsequent IGF-1 generation to maintain compensative hypertrophy by affecting Akt and JNK pathways. Circ Res 105:1149–1158PubMedCrossRefGoogle Scholar
  15. 15.
    Horiuchi-Hirose M, Kashihara T, Nakada T, Kurebayashi N, Shimojo H, Shibazaki T, Sheng X, Yano S, Hirose M, Hongo M, Sakurai T, Moriizumi T, Ueda H, Yamada M (2011) Decrease in the density of t-tubular L-type Ca2+ channel currents in failing ventricular myocytes. Am J Physiol Heart Circ Physiol 300:H978–H988PubMedCrossRefGoogle Scholar
  16. 16.
    House SL, House BE, Glascock B, Kimball T, Nusayr E, Schultz JE, Doetschman T (2010) Fibroblast growth factor 2 mediates isoproterenol-induced cardiac hypertrophy through activation of the extracellular regulated kinase. Mol Cell Pharmacol 2:143–154PubMedGoogle Scholar
  17. 17.
    Kleinbongard P, Heusch G, Schulz R (2010) TNF-α in atherosclerosis, myocardial ischemia/reperfusion and heart failure. Pharmacol Ther 127:295–314PubMedCrossRefGoogle Scholar
  18. 18.
    Liggett SB, Tepe NM, Lorenz JN, Canning AM, Jantz TD, Mitarai S, Yatani A, Dorn GW 2nd (2000) Early and delayed consequences of β(2)-adrenergic receptor overexpression in mouse hearts: critical role for expression level. Circulation 101:1707–1714PubMedGoogle Scholar
  19. 19.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−ΔΔC(T)) method. Methods 25:402–408PubMedCrossRefGoogle Scholar
  20. 20.
    Luo J, Hill BG, Gu Y, Cai J, Srivastava S, Bhatnagar A, Prabhu SD (2007) Mechanisms of acrolein-induced myocardial dysfunction: implications for environmental and endogenous aldehyde exposure. Am J Physiol Heart Circ Physiol 293:H3673–H3684PubMedCrossRefGoogle Scholar
  21. 21.
    Mann DL (2002) Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res 91:988–998PubMedCrossRefGoogle Scholar
  22. 22.
    Mann DL, Bristow MR (2005) Mechanisms and models in heart failure: the biomechanical model and beyond. Circulation 111:2837–2849PubMedCrossRefGoogle Scholar
  23. 23.
    Monden Y, Kubota T, Inoue T, Tsutsumi T, Kawano S, Ide T, Tsutsui H, Sunagawa K (2007) Tumor necrosis factor-α is toxic via receptor 1 and protective via receptor 2 in a murine model of myocardial infarction. Am J Physiol Heart Circ Physiol 293:H743–H753PubMedCrossRefGoogle Scholar
  24. 24.
    Murray DR, Prabhu SD, Chandrasekar B (2000) Chronic β-adrenergic stimulation induces myocardial proinflammatory cytokine expression. Circulation 101:2338–2341PubMedGoogle Scholar
  25. 25.
    Oudit GY, Crackower MA, Eriksson U, Sarao R, Kozieradzki I, Sasaki T, Irie-Sasaki J, Gidrewicz D, Rybin VO, Wada T, Steinberg SF, Backx PH, Penninger JM (2003) Phosphoinositide 3-kinase γ-deficient mice are protected from isoproterenol-induced heart failure. Circulation 108:2147–2152PubMedCrossRefGoogle Scholar
  26. 26.
    Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM (2006) Trends in prevalence and outcome of heart failure with preserved ejection fraction. New Engl J Med 355:251–259PubMedCrossRefGoogle Scholar
  27. 27.
    Palmer JN, Hartogensis WE, Patten M, Fortuin FD, Long CS (1995) Interleukin-1β induces cardiac myocyte growth but inhibits cardiac fibroblast proliferation in culture. J Clin Invest 95:2555–2564PubMedCrossRefGoogle Scholar
  28. 28.
    Prabhu SD (2004) Cytokine-induced modulation of cardiac function. Circ Res 95:1140–1153PubMedCrossRefGoogle Scholar
  29. 29.
    Prabhu SD, Chandrasekar B, Murray DR, Freeman GL (2000) β-adrenergic blockade in developing heart failure: effects on myocardial inflammatory cytokines, nitric oxide, and remodeling. Circulation 101:2103–2109PubMedGoogle Scholar
  30. 30.
    Prabhu SD, Wang G, Luo J, Gu Y, Ping P, Chandrasekar B (2003) β-adrenergic receptor blockade modulates Bcl-X(S) expression and reduces apoptosis in failing myocardium. J Mol Cell Cardiol 35:483–493PubMedCrossRefGoogle Scholar
  31. 31.
    Purcell NH, Tang G, Yu C, Mercurio F, DiDonato JA, Lin A (2001) Activation of NF-κB is required for hypertrophic growth of primary rat neonatal ventricular cardiomyocytes. Proc Natl Acad Sci USA 98:6668–6673PubMedCrossRefGoogle Scholar
  32. 32.
    Qin F, Rounds NK, Mao W, Kawai K, Liang CS (2001) Antioxidant vitamins prevent cardiomyocyte apoptosis produced by norepinephrine infusion in ferrets. Cardiovasc Res 51:736–748PubMedCrossRefGoogle Scholar
  33. 33.
    Ramani R, Mathier M, Wang P, Gibson G, Togel S, Dawson J, Bauer A, Alber S, Watkins SC, McTiernan CF, Feldman AM (2004) Inhibition of tumor necrosis factor receptor-1-mediated pathways has beneficial effects in a murine model of postischemic remodeling. Am J Physiol Heart Circ Physiol 287:H1369–H1377PubMedCrossRefGoogle Scholar
  34. 34.
    Rauchhaus M, Doehner W, Francis DP, Davos C, Kemp M, Liebenthal C, Niebauer J, Hooper J, Volk HD, Coats AJ, Anker SD (2000) Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation 102:3060–3067PubMedGoogle Scholar
  35. 35.
    Reddy VS, Prabhu SD, Mummidi S, Valente AJ, Venkatesan B, Shanmugam P, Delafontaine P, Chandrasekar B (2010) Interleukin-18 induces EMMPRIN expression in primary cardiomyocytes via JNK/Sp1 signaling and MMP-9 in part via EMMPRIN and through AP-1 and NF-κB activation. Am J Physiol Heart Circ Physiol 299:H1242–H1254PubMedCrossRefGoogle Scholar
  36. 36.
    Saadane N, Alpert L, Chalifour LE (1999) Expression of immediate early genes, GATA-4, and Nkx-2.5 in adrenergic-induced cardiac hypertrophy and during regression in adult mice. Br J Pharmacol 127:1165–1176PubMedCrossRefGoogle Scholar
  37. 37.
    Schulz R, Heusch G (2009) Tumor necrosis factor-α and its receptors 1 and 2: Yin and Yang in myocardial infarction? Circulation 119:1355–1357PubMedCrossRefGoogle Scholar
  38. 38.
    Shan J, Kushnir A, Betzenhauser MJ, Reiken S, Li J, Lehnart SE, Lindegger N, Mongillo M, Mohler PJ, Marks AR (2010) Phosphorylation of the ryanodine receptor mediates the cardiac fight or flight response in mice. J Clin Invest 120:4388–4398PubMedCrossRefGoogle Scholar
  39. 39.
    Sharir T, Feldman MD, Haber H, Feldman AM, Marmor A, Becker LC, Kass DA (1994) Ventricular systolic assessment in patients with dilated cardiomyopathy by preload-adjusted maximal power. Validation and noninvasive application. Circulation 89:2045–2053PubMedGoogle Scholar
  40. 40.
    Srivastava S, Chandrasekar B, Gu Y, Luo J, Hamid T, Hill BG, Prabhu SD (2007) Downregulation of CuZn-superoxide dismutase contributes to β-adrenergic receptor-mediated oxidative stress in the heart. Cardiovasc Res 74:445–455PubMedCrossRefGoogle Scholar
  41. 41.
    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 90:807–813PubMedCrossRefGoogle Scholar
  42. 42.
    Venkatachalam K, Prabhu SD, Reddy VS, Boylston WH, Valente AJ, Chandrasekar B (2009) Neutralization of interleukin-18 ameliorates ischemia/reperfusion-induced myocardial injury. J Biol Chem 284:7853–7865PubMedCrossRefGoogle Scholar
  43. 43.
    Wang G, Hamid T, Keith RJ, Zhou G, Partridge CR, Xiang X, Kingery JR, Lewis RK, Li Q, Rokosh DG, Ford R, Spinale FG, Riggs DW, Srivastava S, Bhatnagar A, Bolli R, Prabhu SD (2010) Cardioprotective and antiapoptotic effects of heme oxygenase-1 in the failing heart. Circulation 121:1912–1925PubMedCrossRefGoogle Scholar
  44. 44.
    Yang Z, Zingarelli B, Szabo C (2000) Crucial role of endogenous interleukin-10 production in myocardial ischemia/reperfusion injury. Circulation 101:1019–1026PubMedGoogle Scholar
  45. 45.
    Zhang GX, Kimura S, Nishiyama A, Shokoji T, Rahman M, Yao L, Nagai Y, Fujisawa Y, Miyatake A, Abe Y (2005) Cardiac oxidative stress in acute and chronic isoproterenol-infused rats. Cardiovasc Res 65:230–238PubMedCrossRefGoogle Scholar
  46. 46.
    Zymek P, Nah DY, Bujak M, Ren G, Koerting A, Leucker T, Huebener P, Taffet G, Entman M, Frangogiannis NG (2007) Interleukin-10 is not a critical regulator of infarct healing and left ventricular remodeling. Cardiovasc Res 74:313–322PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Jason B. Garlie
    • 1
    • 2
  • Tariq Hamid
    • 1
  • Yan Gu
    • 1
  • Mohamed Ameen Ismahil
    • 1
  • Bysani Chandrasekar
    • 3
  • Sumanth D. Prabhu
    • 1
    • 2
    • 4
    • 5
  1. 1.Institute of Molecular CardiologyUniversity of LouisvilleLouisvilleUSA
  2. 2.Department of Physiology and BiophysicsUniversity of LouisvilleLouisvilleUSA
  3. 3.Southeast Louisiana Veterans Health Care System, Tulane University School of MedicineNew OrleansUSA
  4. 4.Robley Rex VA Medical CenterLouisvilleUSA
  5. 5.Division of Cardiovascular MedicineUniversity of LouisvilleLouisvilleUSA

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