Skip to main content

Advertisement

SpringerLink
Log in

Dichotomous Actions of NF-κB Signaling Pathways in Heart

  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

Despite the substantial progress in heart research over the past two decades heart failure still remains a major cause of morbidity and mortality in North America and is reaching pandemic proportions worldwide. Though the underlying causes are varied, the functional loss of contractile myocytes through apoptosis, necrosis, and autophagy has emerged a central unifying theme to explain diminished cardiac performance in individuals with heart failure. At the molecular level, there has been considerable interest in understanding the signaling pathways that regulate cell death in the heart with specific interest in the extrinsic and intrinsic cell death pathways. The cellular factor nuclear factor-κB (NF-κB) is a key transcription factor involved in the regulation of a wide range of genes involved in cellular process including inflammation, immune cell maturation, cell proliferation, and, most recently, cell survival. NF-κB signaling is important for the normal cellular growth and is a major target of inflammatory cytokines. Several studies have highlighted a protective role of NF-κB in the heart under certain circumstances including hypoxic or ischemic myocardial injury. The diverse nature and involvement of NF-κB in regulation of vital cellular processes including cell survival notably in the post-mitotic heart has sparked considerable interest in understanding the signaling pathways involved in regulating NF-κB in the heart under normal and pathological conditions. However, whether NF-κB is adaptive, maladaptive or is a homeostatic response to cardiac injury may simply depend on the context and timing of its activation. In this forum we discuss NF-κB signaling pathways and therapeutic opportunities to modulate NF-κB activity in heart failure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ashburner, B. P., Westerheide, S. D., & Baldwin, A. S., Jr. (2001). The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression. Molecular and Cellular Biology, 21, 7065–7077.

    Article  PubMed  CAS  Google Scholar 

  2. Baetu, T. M., Kwon, H., Sharma, S., Grandvaux, N., & Hiscott, J. (2001). Disruption of NF-kappaB signaling reveals a novel role for NF-kappaB in the regulation of TNF-related apoptosis-inducing ligand expression. Journal of Immunology, 167, 3164–3173.

    CAS  Google Scholar 

  3. Baetz, D., Regula, K. M., Ens, K., Shaw, J., Kothari, S., Yurkova, N., et al. (2005). Nuclear factor-kappaB-mediated cell survival involves transcriptional silencing of the mitochondrial death gene BNIP3 in ventricular myocytes. Circulation, 112, 3777–3785.

    Article  PubMed  CAS  Google Scholar 

  4. Baeuerle, P. A., & Baltimore, D. (1989). A 65-kappaD subunit of active NF-kappaB is required for inhibition of NF-kappaB by I kappaB. Genes & Development, 3, 1689–1698.

    Article  CAS  Google Scholar 

  5. Baeuerle, P. A., & Baltimore, D. (1996). NF-kappa B: Ten years after. Cell, 87, 13–20.

    Article  PubMed  CAS  Google Scholar 

  6. Ballard, D. W., Dixon, E. P., Peffer, N. J., Bogerd, H., Doerre, S., Stein, B., et al. (1992). The 65-kDa subunit of human NF-kappa B functions as a potent transcriptional activator and a target for v-Rel-mediated repression. Proceedings of the National Academy of Sciences of the United States of America, 89, 1875–1879.

    Article  PubMed  CAS  Google Scholar 

  7. Beg, A. A., & Baltimore, D. (1996). An essential role for NF-kappaB in preventing TNF-alpha-induced cell death [see comments]. Science, 274, 782–784.

    Article  PubMed  CAS  Google Scholar 

  8. Belosjorow, S., Bolle, I., Duschin, A., Heusch, G., & Schulz, R. (2003). TNF-alpha antibodies are as effective as ischemic preconditioning in reducing infarct size in rabbits. American Journal of Physiology. Heart and Circulatory Physiology, 284, H927–H930.

    PubMed  CAS  Google Scholar 

  9. Bours, V., Azarenko, V., Dejardin, E., & Siebenlist, U. (1994). Human RelB (I-Rel) functions as a kappa B site-dependent transactivating member of the family of Rel-related proteins. Oncogene, 9, 1699–1702.

    PubMed  CAS  Google Scholar 

  10. Brown, K., Gerstberger, S., Carlson, L., Franzoso, G., & Siebenlist, U. (1995). Control of I kappa B-alpha proteolysis by site-specific, signal- induced phosphorylation. Science, 267, 1485–1488.

    Article  PubMed  CAS  Google Scholar 

  11. Brummelkamp, T. R., Nijman, S. M., Dirac, A. M., & Bernards, R. (2003). Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature, 424, 797–801.

    Article  PubMed  CAS  Google Scholar 

  12. Buss, H., Dorrie, A., Schmitz, M. L., Frank, R., Livingstone, M., Resch, K., et al. (2004). Phosphorylation of serine 468 by GSK-3beta negatively regulates basal p65 NF-kappaB activity. The Journal of Biological Chemistry, 279, 49571–49574.

    Article  PubMed  CAS  Google Scholar 

  13. Cain, B. S., Meldrum, D. R., Dinarello, C. A., Meng, X., Joo, K. S., Banerjee, A., et al. (1999). Tumor necrosis factor-alpha and interleukin-1beta synergistically depress human myocardial function [In Process Citation]. Critical Care Medicine, 27, 1309–1318.

    Article  PubMed  CAS  Google Scholar 

  14. Capobianco, A. J., Chang, D., Mosialos, G., & Gilmore, T. D. (1992). p105, the NF-kappa B p50 precursor protein, is one of the cellular proteins complexed with the v-Rel oncoprotein in transformed chicken spleen cells. Journal of Virology, 66, 3758–3767.

    PubMed  CAS  Google Scholar 

  15. Carlotti, F., Dower, S. K., & Qwarnstrom, E. E. (2000). Dynamic shuttling of nuclear factor kappa B between the nucleus and cytoplasm as a consequence of inhibitor dissociation 9. The Journal of Biological Chemistry, 275, 41028–41034.

    Article  PubMed  CAS  Google Scholar 

  16. Catz, S. D., & Johnson, J. L. (2001). Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. Oncogene, 20, 7342–7351.

    Article  PubMed  CAS  Google Scholar 

  17. Chandrasekar, B., & Freeman, G. L. (1997). Induction of nuclear factor kappaB and activation protein 1 in postischemic myocardium. FEBS Letters, 401, 30–34.

    Article  PubMed  CAS  Google Scholar 

  18. Chandrasekar, B., Smith, J. B., & Freeman, G. L. (2001). Ischemia-reperfusion of rat myocardium activates nuclear factor-KappaB and induces neutrophil infiltration via lipopolysaccharide-induced CXC chemokine. Circulation, 103, 2296–2302.

    PubMed  CAS  Google Scholar 

  19. Chen, G., Cao, P., & Goeddel, D. V. (2002). TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90. Molecular Cell, 9, 401–410.

    Article  PubMed  CAS  Google Scholar 

  20. Cleveland, J. L., & Ihle, J. N. (1995). Contenders in FasL/TNF death signaling. Cell, 81, 479–482.

    Article  PubMed  CAS  Google Scholar 

  21. Cogswell, P. C., Scheinman, R. I., & Baldwin, A. S., Jr. (1993). Promoter of the human NF-kappa B p50/p105 gene. Regulation by NF-kappa B subunits and by c-REL. Journal of Immunology, 150, 2794–2804.

    CAS  Google Scholar 

  22. Cosman, D. (1994). A family of ligands for the TNF receptor superfamily. Stem. Cells Dayt., 12, 440–455.

    Article  PubMed  CAS  Google Scholar 

  23. Das, K. C., Lewis-Molock, Y., & White, C. W. (1995). Activation of NF-kappa B and elevation of MnSOD gene expression by thiol reducing agents in lung adenocarcinoma (A549) cells. The American Journal of Physiology, 269, L588–L602.

    PubMed  CAS  Google Scholar 

  24. Dawn, B., Xuan, Y. T., Marian, M., Flaherty, M. P., Murphree, S. S., Smith, T. L., et al. (2001). Cardiac-specific abrogation of NF- kappa B activation in mice by transdominant expression of a mutant I kappa B alpha 20. Journal of Molecular and Cellular Cardiology, 33, 161–173.

    Article  PubMed  CAS  Google Scholar 

  25. de Moissac, D., Mustapha, S., Greenberg, A. H., & Kirshenbaum, L. A. (1998). Bcl-2 activates the transcription factor NFkappaB through the degradation of the cytoplasmic inhibitor IkappaBalpha. The Journal of Biological Chemistry, 273, 23946–23951.

    Article  PubMed  Google Scholar 

  26. de Moissac, D., Zheng, H., & Kirshenbaum, L. A. (1999). Linkage of the BH4 domain of Bcl-2 and the nuclear factor kappaB signaling pathway for suppression of apoptosis. The Journal of Biological Chemistry, 274, 29505–29509.

    Article  PubMed  Google Scholar 

  27. Dejardin, E. (2006). The alternative NF-kappaB pathway from biochemistry to biology: Pitfalls and promises for future drug development. Biochemical Pharmacology, 72, 1161–1179.

    Article  PubMed  CAS  Google Scholar 

  28. Demaria, S., Pikarsky, E., Karin, M., Coussens, L. M., Chen, Y. C., El-Omar, E. M., et al. (2010). Cancer and inflammation: Promise for biologic therapy. Journal of Immunotherapy, 33, 335–351.

    Article  PubMed  Google Scholar 

  29. Dorn, G. W., & Kirshenbaum, L. A. (2008). Cardiac reanimation: Targeting cardiomyocyte death by BNIP3 and NIX/BNIP3L. Oncogene, 27(Suppl 1), S158–S167.

    Article  PubMed  CAS  Google Scholar 

  30. Ellinger Ziegelbauer, H., Brown, K., Kelly, K., & Siebenlist, U. (1997). Direct activation of the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by an inducible mitogen-activated protein Kinase/ERK kinase kinase 3 (MEKK) derivative. The Journal of Biological Chemistry, 272, 2668–2674.

    Article  PubMed  CAS  Google Scholar 

  31. Ganchi, P. A., Sun, S. C., Greene, W. C., & Ballard, D. W. (1992). I kappa B/MAD-3 masks the nuclear localization signal of NF-kappa B p65 and requires the transactivation domain to inhibit NF- kappa B p65 DNA binding. Molecular Biology of the Cell, 3, 1339–1352.

    PubMed  CAS  Google Scholar 

  32. Gilmore, T. D. (1990). NF-kappa B, KBF1, dorsal, and related matters. Cell, 62, 841–843.

    Article  PubMed  CAS  Google Scholar 

  33. Gilmore, T. D., & Morin, P. J. (1993). The I kappa B proteins: Members of a multifunctional family. Trends in Genetics, 9, 427–433.

    Article  PubMed  CAS  Google Scholar 

  34. Hall, J. L., Wang, X., Van, A., Zhao, Y., & Gibbons, G. H. (2001). Overexpression of Ref-1 inhibits hypoxia and tumor necrosis factor-induced endothelial cell apoptosis through nuclear factor-kappab-independent and -dependent pathways. Circulation Research, 88, 1247–1253.

    Article  PubMed  CAS  Google Scholar 

  35. Hamid, T., Gu, Y., Ortines, R. V., Bhattacharya, C., Wang, G., Xuan, Y. T., et al. (2009). Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: Role of nuclear factor-kappaB and inflammatory activation. Circulation, 119, 1386–1397.

    Article  PubMed  CAS  Google Scholar 

  36. Haudek, S. B., Spencer, E., Bryant, D. D., White, D. J., Maass, D., Horton, J. W., et al. (2001). Overexpression of cardiac I-kappaBalpha prevents endotoxin-induced myocardial dysfunction. American Journal of Physiology. Heart and Circulatory Physiology, 280, H962–H968.

    PubMed  CAS  Google Scholar 

  37. Hayakawa, Y., Chandra, M., Miao, W., Shirani, J., Brown, J. H., Dorn, G. W., et al. (2003). Inhibition of cardiac myocyte apoptosis improves cardiac function and abolishes mortality in the peripartum cardiomyopathy of Galpha(q) transgenic mice. Circulation, 108, 3036–3041.

    Article  PubMed  CAS  Google Scholar 

  38. Hayden, M. S., & Ghosh, S. (2004). Signaling to NF-kappaB. Genes & Development, 18, 2195–2224.

    Article  CAS  Google Scholar 

  39. Herskowitz, A., Choi, S., Ansari, A. A., & Wesselingh, S. (1995). Cytokine mRNA expression in postischemic/reperfused myocardium. The American Journal of Pathology, 146, 419–428.

    PubMed  CAS  Google Scholar 

  40. Hoffmann, A., & Baltimore, D. (2006). Circuitry of nuclear factor kappaB signaling. Immunological Reviews, 210, 171–186.

    Article  PubMed  Google Scholar 

  41. Hoffmann, A., Natoli, G., & Ghosh, G. (2006). Transcriptional regulation via the NF-kappaB signaling module. Oncogene, 25, 6706–6716.

    Article  PubMed  CAS  Google Scholar 

  42. Hsu, H., Shu, H. B., Pan, M. G., & Goeddel, D. V. (1996). TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell, 84, 299–308.

    Article  PubMed  CAS  Google Scholar 

  43. Hsu, H., Xiong, J., & Goeddel, D. V. (1995). The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell, 81, 495–504.

    Article  PubMed  CAS  Google Scholar 

  44. Hu, Y., Baud, V., Oga, T., Kim, K. I., Yoshida, K., & Karin, M. (2001). IKKalpha controls formation of the epidermis independently of NF-kappaB. Nature, 410, 710–714.

    Article  PubMed  CAS  Google Scholar 

  45. Karin, M. (2009). NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol, 1, a000141.

    Article  PubMed  CAS  Google Scholar 

  46. Karin, M., & Lin, A. (2002). NF-kappaB at the crossroads of life and death. Nature Immunology, 3, 221–227.

    Article  PubMed  CAS  Google Scholar 

  47. Kasibhatla, S., Genestier, L., & Green, D. R. (1999). Regulation of fas-ligand expression during activation-induced cell death in T lymphocytes via nuclear factor kappaB. The Journal of Biological Chemistry, 274, 987–992.

    Article  PubMed  CAS  Google Scholar 

  48. Kurrelmeyer, K. M., Michael, L. H., Baumgarten, G., Taffet, G. E., Peschon, J. J., Sivasubramanian, N., et al. (2000). Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction. Proceedings of the National Academy of Sciences of the United States of America, 97, 5456–5461.

    Article  PubMed  CAS  Google Scholar 

  49. Li, X., He, D., Zhang, L., Xue, Y., Cheng, X., & Luo, Y. (2007). Pyrrolidine dithiocarbamate attenuate shock wave induced MDCK cells injury via inhibiting nuclear factor-kappa B activation. Urological Research, 35, 193–199.

    Article  PubMed  CAS  Google Scholar 

  50. Libermann, T. A., & Baltimore, D. (1990). Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Molecular and Cellular Biology, 10, 2327–2334.

    PubMed  CAS  Google Scholar 

  51. Luss, H., Schmitz, W., & Neumann, J. (2002). A proteasome inhibitor confers cardioprotection. Cardiovascular Research, 54, 140–151.

    Article  PubMed  CAS  Google Scholar 

  52. Madrid, L. V., Wang, C. Y., Guttridge, D. C., Schottelius, A. J., Baldwin, A. S., Jr., & Mayo, M. W. (2000). Akt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NF-kappaB. Molecular and Cellular Biology, 20, 1626–1638.

    Article  PubMed  CAS  Google Scholar 

  53. Maekawa, N., Wada, H., Kanda, T., Niwa, T., Yamada, Y., Saito, K., et al. (2002). Improved myocardial ischemia/reperfusion injury in mice lacking tumor necrosis factor-alpha. Journal of the American College of Cardiology, 39, 1229–1235.

    Article  PubMed  CAS  Google Scholar 

  54. Matsui, T., Li, L., del, M., Fukui, Y., Franke, T. F., Hajjar, R. J., et al. (1999). Adenoviral gene transfer of activated phosphatidylinositol 3'-kinase and Akt inhibits apoptosis of hypoxic cardiomyocytes in vitro. Circulation, 100, 2373–2379.

    PubMed  CAS  Google Scholar 

  55. Matsushita, H., Morishita, R., Nata, T., Aoki, M., Nakagami, H., Taniyama, Y., et al. (2000). Hypoxia-induced endothelial apoptosis through nuclear factor-kappaB (NF-kappaB)-mediated bcl-2 suppression: In vivo evidence of the importance of NF-kappaB in endothelial cell regulation. Circulation Research, 86, 974–981.

    PubMed  CAS  Google Scholar 

  56. McKinsey, T. A., Chu, Z. L., & Ballard, D. W. (1997). Phosphorylation of the PEST domain of IkappaBbeta regulates the function of NF-kappaB/IkappaBbeta complexes. The Journal of Biological Chemistry, 272, 22377–22380.

    Article  PubMed  CAS  Google Scholar 

  57. Meldrum, D. R., Meng, X., Dinarello, C. A., Ayala, A., Cain, B. S., Shames, B. D., et al. (1998). Human myocardial tissue TNFalpha expression following acute global ischemia in vivo. Journal of Molecular and Cellular Cardiology, 30, 1683–1689.

    Article  PubMed  CAS  Google Scholar 

  58. Micheau, O., Lens, S., Gaide, O., Alevizopoulos, K., & Tschopp, J. (2001). NF-kappaB signals induce the expression of c-FLIP. Molecular and Cellular Biology, 21, 5299–5305.

    Article  PubMed  CAS  Google Scholar 

  59. Misra, A., Haudek, S. B., Knuefermann, P., Vallejo, J. G., Chen, Z. J., Michael, L. H., et al. (2003). Nuclear factor-kappaB protects the adult cardiac myocyte against ischemia-induced apoptosis in a murine model of acute myocardial infarction 1. Circulation, 108, 3075–3078.

    Article  PubMed  CAS  Google Scholar 

  60. Moss, N. C., Stansfield, W. E., Willis, M. S., Tang, R. H., & Selzman, C. H. (2007). IKKbeta inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury. American Journal of Physiology. Heart and Circulatory Physiology, 293, H2248–H2253.

    Article  PubMed  CAS  Google Scholar 

  61. Mustapha, S., Kirshner, A., de Moissac, D., & Kirshenbaum, L. A. (2000). A direct requirement of nuclear factor-kappa B for suppression of apoptosis in ventricular myocytes. American Journal of Physiology. Heart and Circulatory Physiology, 279, H939–H945.

    PubMed  CAS  Google Scholar 

  62. Nadal-Ginard, B. (1978). Commitment, fusion and biochemical differentiation of a myogenic cell line in the absence of DNA synthesis 1. Cell, 15, 855–864.

    Article  PubMed  CAS  Google Scholar 

  63. Nakano, M., Knowlton, A. A., Dibbs, Z., & Mann, D. L. (1998). Tumor necrosis factor-alpha confers resistance to hypoxic injury in the adult mammalian cardiac myocyte. Circulation, 97, 1392–1400.

    PubMed  CAS  Google Scholar 

  64. Narula, J., Haider, N., Virmani, R., DiSalvo, T. G., Kolodgie, F. D., Hajjar, R. J., et al. (1996). Apoptosis in myocytes in end-stage heart failure [see comments]. The New England Journal of Medicine, 335, 1182–1189.

    Article  PubMed  CAS  Google Scholar 

  65. Neumann, F. J., Ott, I., Gawaz, M., Richardt, G., Holzapfel, H., Jochum, M., et al. (1995). Cardiac release of cytokines and inflammatory responses in acute myocardial infarction. Circulation, 92, 748–755.

    PubMed  CAS  Google Scholar 

  66. Olivetti, G., Abbi, R., Quaini, F., Kajstura, J., Cheng, W., Nitahara, J. A., et al. (1997). Apoptosis in the failing human heart. The New England Journal of Medicine, 336, 1131–1141.

    Article  PubMed  CAS  Google Scholar 

  67. Opipari, A. W., Jr., Hu, H. M., Yabkowitz, R., & Dixit, V. M. (1992). The A20 zinc finger protein protects cells from tumor necrosis factor cytotoxicity. The Journal of Biological Chemistry, 267, 12424–12427.

    PubMed  CAS  Google Scholar 

  68. Polunovsky, V. A., Wendt, C. H., Ingbar, D. H., Peterson, M. S., & Bitterman, P. B. (1994). Induction of endothelial cell apoptosis by TNF alpha: Modulation by inhibitors of protein synthesis. Experimental Cell Research, 214, 584–594.

    Article  PubMed  CAS  Google Scholar 

  69. Poyet, J. L., Srinivasula, S. M., Lin, J. H., Fernandes-Alnemri, T., Yamaoka, S., Tsichlis, P. N., et al. (2000). Activation of the Ikappa B kinases by RIP via IKKgamma/NEMO-mediated oligomerization. The Journal of Biological Chemistry, 275, 37966–37977.

    Article  PubMed  CAS  Google Scholar 

  70. Purcell, N. H., Tang, G., Yu, C., Mercurio, F., DiDonato, J. A., & Lin, A. (2001). Activation of NF-kappa B is required for hypertrophic growth of primary rat neonatal ventricular cardiomyocytes. Proceedings of the National Academy of Sciences of the United States of America, 98, 6668–6673.

    Article  PubMed  CAS  Google Scholar 

  71. Pye, J., Ardeshirpour, F., McCain, A., Bellinger, D. A., Merricks, E., Adams, J., et al. (2003). Proteasome inhibition ablates activation of NF-kappa B in myocardial reperfusion and reduces reperfusion injury. American Journal of Physiology. Heart and Circulatory Physiology, 284, H919–H926.

    PubMed  CAS  Google Scholar 

  72. Regula, K. M., Baetz, D., & Kirshenbaum, L. A. (2004). Nuclear factor-kappaB represses hypoxia-induced mitochondrial defects and cell death of ventricular myocytes 2. Circulation, 110, 3795–3802.

    Article  PubMed  CAS  Google Scholar 

  73. Rius, J., Guma, M., Schachtrup, C., Akassoglou, K., Zinkernagel, A. S., Nizet, V., et al. (2008). NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature, 453, 807–811.

    Article  PubMed  CAS  Google Scholar 

  74. Robaye, B., Mosselmans, R., Fiers, W., Dumont, J. E., & Galand, P. (1991). Tumor necrosis factor induces apoptosis (programmed cell death) in normal endothelial cells in vitro. The American Journal of Pathology, 138, 447–453.

    PubMed  CAS  Google Scholar 

  75. Sen, R., & Baltimore, D. (1986). Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell, 46, 705–716.

    Article  PubMed  CAS  Google Scholar 

  76. Senftleben, U., Cao, Y., Xiao, G., Greten, F. R., Krahn, G., Bonizzi, G., et al. (2001). Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science, 293, 1495–1499.

    Article  PubMed  CAS  Google Scholar 

  77. Shaw, J., Yurkova, N., Zhang, T., Gang, H., Aguilar, F., Weidman, D., et al. (2008). Antagonism of E2F-1 regulated Bnip3 transcription by NF-kappaB is essential for basal cell survival. Proceedings of the National Academy of Sciences of the United States of America, 105, 20734–20739.

    Article  PubMed  Google Scholar 

  78. Shimizu, M., Tamamori-Adachi, M., Arai, H., Tabuchi, N., Tanaka, H., & Sunamori, M. (2002). Lipopolysaccharide pretreatment attenuates myocardial infarct size: A possible mechanism involving heat shock protein 70-inhibitory kappaBalpha complex and attenuation of nuclear factor kappaB. The Journal of Thoracic and Cardiovascular Surgery, 124, 933–941.

    Article  PubMed  CAS  Google Scholar 

  79. Sif, S., & Gilmore, T. D. (1993). NF-kappa B p100 is one of the high-molecular-weight proteins complexed with the v-Rel oncoprotein in transformed chicken spleen cells. Journal of Virology, 67, 7612–7617.

    PubMed  CAS  Google Scholar 

  80. Song, H. Y., Rothe, M., & Goeddel, D. V. (1996). The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation. Proceedings of the National Academy of Sciences of the United States of America, 93, 6721–6725.

    Article  PubMed  CAS  Google Scholar 

  81. Sun, S. C., Ganchi, P. A., Ballard, D. W., & Greene, W. C. (1993). NF-kappa B controls expression of inhibitor I kappa B alpha: Evidence for an inducible autoregulatory pathway. Science, 259, 1912–1915.

    Article  PubMed  CAS  Google Scholar 

  82. Takeda, K., Takeuchi, O., Tsujimura, T., Itami, S., Adachi, O., Kawai, T., et al. (1999). Limb and skin abnormalities in mice lacking IKKalpha. Science, 284, 313–316.

    Article  PubMed  CAS  Google Scholar 

  83. Tanaka, M., Fuentes, M. E., Yamaguchi, K., Durnin, M. H., Dalrymple, S. A., Hardy, K. L., et al. (1999). Embryonic lethality, liver degeneration, and impaired NF-kappa B activation in IKK-beta-deficient mice. Immunity, 10, 421–429.

    Article  PubMed  CAS  Google Scholar 

  84. Torre-Amione, G., Kapadia, S., Benedict, C., Oral, H., Young, J. B., & Mann, D. L. (1996). Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: A report from the Studies of Left Ventricular Dysfunction (SOLVD). Journal of the American College of Cardiology, 27, 1201–1206.

    Article  PubMed  CAS  Google Scholar 

  85. Torre-Amione, G., Kapadia, S., Lee, J., Durand, J. B., Bies, R. D., Young, J. B., et al. (1996). Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation, 93, 704–711.

    PubMed  CAS  Google Scholar 

  86. Van Antwerp, D. J., Martin, S. J., Kafri, T., Green, D. R., & Verma, I. M. (1996). Suppression of TNF-alpha-induced apoptosis by NF-kappaB [see comments]. Science, 274, 787–789.

    Article  PubMed  Google Scholar 

  87. Van Antwerp, D. J., & Verma, I. M. (1996). Signal-induced degradation of I(kappa)B(alpha): Association with NF-kappaB and the PEST sequence in I(kappa)B(alpha) are not required. Molecular and Cellular Biology, 16, 6037–6045.

    PubMed  Google Scholar 

  88. van, U. P., Kenneth, N. S., & Rocha, S. (2008). Regulation of hypoxia-inducible factor-1alpha by NF-kappaB. The Biochemical Journal, 412, 477–484.

    Article  Google Scholar 

  89. Verma, I. M., Stevenson, J. K., Schwarz, E. M., Van Antwerp, D., & Miyamoto, S. (1995). Rel/NF-kappa B/I kappa B family: Intimate tales of association and dissociation. Genes & Development, 9, 2723–2735.

    Article  CAS  Google Scholar 

  90. Wang, C. Y., Guttridge, D. C., Mayo, M. W., & Baldwin, A. S., Jr. (1999). NF-kappaB induces expression of the bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis [In Process Citation]. Molecular and Cellular Biology, 19, 5923–5929.

    PubMed  CAS  Google Scholar 

  91. Wang, C. Y., Mayo, M. W., & Baldwin, A. S., Jr. (1996). TNF- and cancer therapy-induced apoptosis: Potentiation by inhibition of NF-kappaB [see comments]. Science, 274, 784–787.

    Article  PubMed  CAS  Google Scholar 

  92. Wang, C. Y., Mayo, M. W., Korneluk, R. G., Goeddel, D. V., & Baldwin, A. S., Jr. (1998). NF-kappaB antiapoptosis: Induction of TRAF1 and TRAF2 and c-IAP1 and c- IAP2 to suppress caspase-8 activation. Science, 281, 1680–1683.

    Article  PubMed  CAS  Google Scholar 

  93. Wencker, D., Chandra, M., Nguyen, K., Miao, W., Garantziotis, S., Factor, S. M., et al. (2003). A mechanistic role for cardiac myocyte apoptosis in heart failure. Journal of Clinical Investigation, 111, 1497–1504.

    PubMed  CAS  Google Scholar 

  94. Wertz, I. E., O'Rourke, K. M., Zhou, H., Eby, M., Aravind, L., Seshagiri, S., et al. (2004). De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature, 430, 694–699.

    Article  PubMed  CAS  Google Scholar 

  95. Wong, S. C., Fukuchi, M., Melnyk, P., Rodger, I., & Giaid, A. (1998). Induction of cyclooxygenase-2 and activation of nuclear factor-kappaB in myocardium of patients with congestive heart failure. Circulation, 98, 100–103.

    PubMed  CAS  Google Scholar 

  96. Wu, X., & Levine, A. J. (1994). p53 and E2F-1 cooperate to mediate apoptosis. Proceedings of the National Academy of Sciences of the United States of America, 91, 3602–3606.

    Article  PubMed  CAS  Google Scholar 

  97. Yin, M. J., Yamamoto, Y., & Gaynor, R. B. (1998). The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature, 396, 77–80.

    Article  PubMed  CAS  Google Scholar 

  98. Zak, R. (1974). Development and proliferative capacity of cardiac muscle cells. Circulation Research, 2, 17–26.

    Google Scholar 

  99. Zhang, J., Ping, P., Vondriska, T. M., Tang, X. L., Wang, G. W., Cardwell, E. M., et al. (2003). Cardioprotection involves activation of NF-kappa B via PKC-dependent tyrosine and serine phosphorylation of I kappa B-alpha. American Journal of Physiology. Heart and Circulatory Physiology, 285, H1753–H1758.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to Dr. H. Weisman for critical comments on the manuscript. Pam Lowe for editorial assistance and manuscript preparation; Floribeth Aguilar, Hongying Gang for technical assistance. R.D. holds a post-doctoral fellowship from the Manitoba Health Research Council. This work was supported by grants to L.A.K from the CIHR and St. Boniface Hospital Research Foundation, L.A.K. holds a Canada Research Chair in Molecular Cardiology.

Author information

Authors and Affiliations

  1. The Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Department of Physiology, Faculty of Medicine, University of Manitoba, Rm. 3016, 351 TachéAvenue, Winnipeg, MB, R2H 2A6, Canada

    Rimpy Dhingra, James A. Shaw, Yaron Aviv & Lorrie A. Kirshenbaum

  2. The Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, MB, R2H 2A6, Canada

    Lorrie A. Kirshenbaum

Authors
  1. Rimpy Dhingra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James A. Shaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yaron Aviv
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lorrie A. Kirshenbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lorrie A. Kirshenbaum.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dhingra, R., Shaw, J.A., Aviv, Y. et al. Dichotomous Actions of NF-κB Signaling Pathways in Heart. J. of Cardiovasc. Trans. Res. 3, 344–354 (2010). https://doi.org/10.1007/s12265-010-9195-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-010-9195-5

Keywords

Search

Navigation