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NF-κB as an integrator of diverse signaling pathways

The heart of myocardial signaling?

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Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

NF-κB is a pleiotropic transcription factor implicated in the regulation of diverse biological phenomena, including apoptosis, cell survival, cell growth, cell division, innate immunity, cellular differentiation, and the cellular responses to stress, hypoxia, stretch and ischemia. In the heart, NF-κB has been shown to be activated in atherosclerosis, myocarditis, in association with angina, during transplant rejection, after ischemia/ reperfusion, in congestive heart failure, dilated cardiomyopathy, after ischemic and pharmacological preconditioning, heat shock, burn trauma, and in hypertrophy of isolated cardiomyocytes. Regulation of NF-κB is complicated; in addition to being activated by canonical cytokine-mediated pathways, NF-κB is activated by many of the signal transduction cascades associated with the development of cardiac hypertrophy and response to oxidative stress. Many of these signaling cascades activate NF-κB by activating the lκB kinase (IKK) complex a major component of the canonical pathway. These signaling interactions occur largely via signaling crosstalk involving the mitogen-activated protein kinase/extracellular signaling crosstalk involving the mitogen-activated protein kinase/extracellular signal-regulated kinases (MEKKs) that are components of mitogen activated protein kinase (MAPK) signaling pathways. Additionally, there are other signaling factors that act more directly to activate NF-κB via IκB or by direct phosphorylation of NF-κB subunits. Finally, there are combinatorial interactions at the level of the promoter between NF-κB, its, coativators, and other transcription factors, several of which are activated by MAPK and cytokine signaling pathways. Thus, in addition to being a major mediator of cytokine effects in the heart, NF-κB is positioned as a signaling integrator. As such, NF-κB functions as a key regulator of cardiac gene expression programs downstream of multiple signal transduction cascades in a variety of physiological and pathophysiological states. We show that genetic blockade of NF-κB reduces infarct size in the murine heart after ischemia/reperfusion (I/R), implicating NF-κB as a major determinant of cell death after I/R. These results support the concept that NF-κB may be an important therapeutic target for specific cardiovascular diseases. Furthermore, undertanding the complex signal transduction and gene regulation networks associated with NF-κB functionality will allow us to identify the discrete sets of NF-κB-dependent genes that affect specific pathophysiological phenomena. These genes may be even better therapeutic targets, allowing us to block the injurious effects while preserving the potentially beneficial effects of adaptive signaling in the heart.

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References

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

    PubMed  CAS  Google Scholar 

  2. Baldwin, A.S., Jr. (1996). The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu. Rev. Immunol. 14:649–683.

    PubMed  CAS  Google Scholar 

  3. Parry, G. and Mackman, N. (1994). A set of inducible genes expressed by activated human monocytic and endothelial cells contain κB-like sites that specifically bind c-Rel-p65 heterodimers. J. Biol. Chem. 269:20823–20825.

    PubMed  CAS  Google Scholar 

  4. Knuefermann, P., Chen, P., Misra, A., Shi, S.P., Abdellatif, M., and Sivasubrananian, N. (2002). Myotrophin/V-1, a protein up-regulated in the failing human heart and in postnatal cerebellum, converts NFkappa B p50-p65 heterodimers to p50-p50 and p65-p65 homodimers. J. Biol. Chem. 277:23888–23897.

    PubMed  CAS  Google Scholar 

  5. Dawn, B., Xuan Y.T., Marian, M., et al. (2001). Cardiac-specific Abrogation of NF-kappab activation in mice by transdominant expression of a mutant Ikappa-Balpha. J. Mol. Cell. Cardiol. 33:161–173.

    PubMed  CAS  Google Scholar 

  6. Haudek, S.B., Bryant, D.D., and Giroir, B.P. (2001). Differential regulation of myocardial NF kappa B following acute or chronic TNF-alpha exposure. J. Mol. Cell Cardiol. 33:1263–1271.

    PubMed  CAS  Google Scholar 

  7. Haudek, S.B., Spencer, E., Bryant, D.D., et al. (2001). Overexpression of cardiac I-kappaBalpha prevents endotoxin-induced myocardial dysfunction. Am. J. Physiol. Heart Circ. Physiol., 280:H962-H968.

    PubMed  CAS  Google Scholar 

  8. Kubota, T., Miyagishima, M., Frye, C., et al. (2001). Overex pression of tumornecrosis alpha activates both anti-and pro-apoptotic pathways in the myocardium. JMCC 33: 1331–1344.

    CAS  Google Scholar 

  9. Baldwin, A.S., Jr. (2001). The transcription factor NF-κB and human disease. JCI 107:3–6.

    PubMed  CAS  Google Scholar 

  10. Regula, K.M., Ens, K., and Kirshenbaum, L.A. (2002). IKK beta is required for Gcl-2-mediated NF-kappa B activation in ventricular myocytes. J. Biol. Chem. 277: 38676–38682.

    PubMed  CAS  Google Scholar 

  11. Zingarelli, B., Hake, P.W., Yang, Z., O’Connor, M., Denenberg, A., and Wong, H.R. (2002). Absence of inducible nitric oxide synthase modulates early reperfusion-induced NF-kappaB and AP-1 activation and enhances myocardial damage. FASEB J. 16:327–342.

    PubMed  CAS  Google Scholar 

  12. Abu-Amer, Y., Ross, F.P., McHugh, K.P., et al. (1998). Tumor necrosis factor-α activation of nuclear transcription factor-κB in marrow macrophages is mediated by c-Src tyrosine phosphorylation of IκB α. JBC 273:29417–29423.

    CAS  Google Scholar 

  13. Diaz-Guerra, M.J., Castrillo, A., Martin-Sanz P., and Bosca, L. (1999). Negative regulation by protein tyrosine phosphatase of IFN-gamma-dependent expression of induciblenitric oxidase synthase. J Immunol. 162:6776–6783.

    PubMed  CAS  Google Scholar 

  14. Livolsi, A., Busuttil, V., Imbert, V., Abraham, R.T., and Peyron, J.F. (2001). Tyrosine phosphorylation-dependent activation of NF-kappa B. Requirement for p56 LCK and ZaP-70 protein tyrosine kinases Eur J. Biochem. 268:1508–1515.

    PubMed  CAS  Google Scholar 

  15. Birbach, A., Gold, P., Binder, B.R., Hofer, E., de Martin, R., and Schmidt, J. A. (2002). Signaling molecules of the NF-κB pathway shuttle consititutively between cytoplasm and nucleus. JBC 277:10842–10851.

    CAS  Google Scholar 

  16. Carlotti, F., Dower, S.K., and Qwarnstrom, E.E. (2000). Dynamic shuttling of nuclear factor kappa B between the nucleus and cytoplasm as a consequence of inhibitor dissociation. J. Biol. Chem. 275:41028–41034.

    PubMed  CAS  Google Scholar 

  17. Arenzana-Seisdedos, F., Thompson, J., Rodriguez, M.S., et al. (1995). Inducible nuclear expression of newly synthesized Ikappa B alpha negatively regulates DNA-binding and transcriptional activities of NF-kappa B. Mol. Cell. Biol. 15: 2689–2696.

    PubMed  CAS  Google Scholar 

  18. Wen, W., Meinkoth, J. L., Tsien, R.Y., and Taylor, S.S. (1995). Identification of a signal for rapid export of proteins from the nucleus. Cell 82:463–473.

    PubMed  CAS  Google Scholar 

  19. Suyang, H., Phillips, R., Douglas, I., and Ghosh, S. (1996). Role of unphosphorylated, newly synthesized I kappa B beta in persistent activation of NF-kappa B. Mol. Cell. Biol. 16:5444–5449.

    PubMed  CAS  Google Scholar 

  20. Baeuerle, P., and Henkel, T. (1994). Function and activation of NF-κB in the immune system. Annu. Rev. Immunol. 12:141–179.

    PubMed  CAS  Google Scholar 

  21. Siebenlist, U., Franzoso, G., and Brown, K. (1994). Structure, regulation and function of NF-κB. Annu. Rev. Cell Biol. 10:405–455.

    PubMed  CAS  Google Scholar 

  22. Hoffman, A., Levchenko, A., Scott, M.L., and Baltimore, D. (2002). The Ikkapa B-NF-kappa B signaling module: temporal control and selective gene activation. Science 298:1241–1245.

    Google Scholar 

  23. Chandrasekar, B. and Freemen, G.L. (1997). Induction of nuclear factor-kappa B and activation factor 1 in postischemic myocardium. FEBS Lett. 401:30–34.

    PubMed  CAS  Google Scholar 

  24. Ladner, K.J., Caligiuri, M.A., and Guttridge D.C. (2003). Tumor necrosis factor-regulated biphasic activation of NF-kappa B is required for cytokine-induced loss of skeletal muscle gene products. JBC 278:2294–2303.

    CAS  Google Scholar 

  25. Lille, S.T., Lefler, S.R., Mowlavi, A., et al. (2001). Inhibition of the initial wave of NF-kappa B activity in rat muscle reduces ischemia/reperfusion injury. Muscle Nerve 24:534–541.

    PubMed  CAS  Google Scholar 

  26. Li C, Kao, R.L., Ha, T., Kelley, J., Browder, I.W., and Williams, D.L. (2001). Early activation of IK κBeta during in vivo myocardial ischemia. Am. J. Physiol. Heart Circ. Physiol. 280:H1264-H1271.

    PubMed  CAS  Google Scholar 

  27. Condorelli, G., Morisco, C., Latronico, M.V., et al. (2002). TNF-alpha signal transduction in rat neonatal cardiac myocytes: definition of pathways generating from the TNF-alpha receptor. FASEB J 16:1732–1737.

    PubMed  CAS  Google Scholar 

  28. Craig, R., Wagner, M., McCardle, T, Craig, A. G., and Glembotski, C.C. (2001). The cytoprotective effects of the glycoprotein 130 receptor-coupled cytokine, cardiotrophin-1, require activation of NF-kappa B. J. Biol. Chem. 276:37621–37629.

    PubMed  CAS  Google Scholar 

  29. Maulik, N., Sato, M., Price, B.D., and Das, D.K. (1998). An essential role of NF kappa B in tyrosine kinase signaling of p38 MAP kinase regulation of myocardial adaptation to ischemia. FEBS Lett. 429:365–369.

    PubMed  CAS  Google Scholar 

  30. Zechner, D., Craig, R., Hanford, D.S., McDonough, P.M., Sabbadini, R.A., and Glembotski, C.C. (1998). MKK6 activates myocardial cell NF-kappaB and inhibits apoptosis in a p38 mitogen-activated protein kinase-dependent manner. J. Biol. Chem. 273:8232–8239.

    PubMed  CAS  Google Scholar 

  31. Force, T., Haq, S., Kilter, H., and Michael, A. (2002). Apoptosis signal-regulating kinase/nuclear factor-kappaB: a novel signaling pathway regulates cardiomyocyte hypertrophy. Circulation 105:402–404.

    PubMed  CAS  Google Scholar 

  32. Hirotani, S., Otsu, K., Nishida, K., et al. (2002). Involvement of nuclear factor-kappaB and apoptosis signal-regulating kinase 1 in G-protein-coupled receptor agonist-induced cardiomyocyte hypertrophy. Circulation 105:509–515.

    PubMed  CAS  Google Scholar 

  33. Lee, F.S., Hagler, J., Chen, Z.J., and Maniatis, T. (1997). Activation of the IkappaB alpha kinase complex by MEKK1, a kinase of the JNK pathway. Cell 88:213–222.

    PubMed  CAS  Google Scholar 

  34. Lee, F.S., Peters, R.T., Dang, L.C., and Maniatis, T. (1998). MEKK1 activates both I-kappaB kinase alpha and I-kappaB kinase beta. PNAS 95:9319–9324.

    PubMed  CAS  Google Scholar 

  35. Vanden Berghe, W., Plaisance, S., Boone, E., et al. (1998). p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways are required for nuclear factor-kappaB p65 transactivation mediated by tumor necrosis factor. J. Biol. Chem. 273:3285–3290.

    Google Scholar 

  36. Wesselborg, S., Bauer, M.K., Vogt, M., Schmitz, M.L., and Schulze-Osthoff, K. (1997). Activation of transcription factor NF-kappaB and p38 mitogen-activated protein kinase is mediated by distinct and separate stress effector pathways. J. Biol. Chem. 272:12422–12429.

    PubMed  CAS  Google Scholar 

  37. Yang, J., Fan, G.H., Wadzinski, B.E., Sakurai, H., and Richmond, A. (2001). Protein phosphatase 2A interacts with and directly dephosphorylates RelA. J. Biol. Chem. 276:47828–47833.

    PubMed  CAS  Google Scholar 

  38. Zhao, X. and Eghbali-Webb, M. (2002). Gender-related differences in basal and hypoxia-induced activation of signal transduction pathways controlling cell cycle progression and apoptosis, in cardiac fibroblasts. Endocrine 18:137–145.

    PubMed  CAS  Google Scholar 

  39. Huynh, Q.K., Boddupalli, H., Rouw, S.A., et al. (2000). Characterization of the recombinant IKK1/IKK2 heterodimer. Mechanisms regulating kinase activity. J. Biol. Chem. 275:25883–25891.

    PubMed  CAS  Google Scholar 

  40. Peters, R.T., Liao, S.M., and Maniatis, T. (2000). IKK-epsilon is part of a novel PMA-inducible Ikappa-B kinase complex. Mol. Cell. 5:513–522.

    PubMed  CAS  Google Scholar 

  41. Shimada, T., Kawai, T., Takeda, K., et al. (1999). IKK-I, a novel lipopolysaccharide inducible kinase that is related to IkappaB kinases. Int. Immunol. 11:1357–1362.

    PubMed  CAS  Google Scholar 

  42. Valen, G., Yan, Z., and Hansson, G.K. (2001). Nuclear factor kappaB and the heart. JACC 38:307–314.

    PubMed  CAS  Google Scholar 

  43. Janssen-Heininger, Y.M., Pointer, M.E., and Baeuerle, P.A. (2000). Recent advances towards understanding redox mechanisms in the activation of nuclear factor κB. Free Rad. Biol. Med. 28:1317–1327.

    PubMed  CAS  Google Scholar 

  44. Wang, D. and Baldwin, A.S. Jr. (1998). Activation of nuclear factor-kappaB-dependent transcription by tumor necrosis factor-alpha is mediated through phosphorylation of RelA/p65 on serine 529. J. Biol. Chem. 273: 29411–29416.

    PubMed  CAS  Google Scholar 

  45. Sakurai, H., Chiba, H., Miyoshi, H., Sugita, T., and Toruimi, W. (1999). lκB kinases phosphorylate NF-κB p65 subunit on serine 536 in the transactivation domain. JBC 274:30353–30356.

    CAS  Google Scholar 

  46. Sizemore, N., Lerner, N., Dombrowski, N., Sakurai, H., and Stark, G.R. (2002). Distinct roles of the Ikappa B kinase alpha and beta subunits in liberating nuclear factor kappa B (NF-kappa B) from Ikappa B and in phosphorylating the p64 subunit of NF-kappa B. J. Biol. Chem. 277: 3863–3869.

    PubMed  CAS  Google Scholar 

  47. Sizemore, N., Leung, S., and Stark, G.R. (1999). Activation of phosphatidylinositol 3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-kappaB p65/RelA subunit. Mol. Cell. Biol. 19:4798–4805.

    PubMed  CAS  Google Scholar 

  48. Anrather, J., Csizmadia, V., Soares, M.P., and Winkler, H. (1999). Regulation of NF-kappaB RelA phosphorylation and transcriptional activity by p21(ras) and protein kinase Czeta in primaryendothelial cells. J. Biol. Chem. 274:13594–13603.

    PubMed  CAS  Google Scholar 

  49. Leitges, M., Sanz, L., Martin, P., et al. (2001). Targeted disruption of the zetaPKC gene results in the impairment of the NF-kappaB pathway. Mol. Cell. 8:771–780.

    PubMed  CAS  Google Scholar 

  50. Zhong, H., Voll, R.E., and Ghosh, S. (1998). Phosphorylation of NF-kappa B p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. Mol. Cell. 1:661–671.

    PubMed  CAS  Google Scholar 

  51. Karin, M. and Ben-Neriah, Y. (2000). Phosphorylation meets ubiquitination: the control of NF-κB activity. Ann. Rev. Immun. 18:621–623.

    CAS  Google Scholar 

  52. Vermeulin, L., De Wilde, G., Notebaert, S., Berghe, W.V., and Haegeman, G. (2002). Regulation of the transcriptional activity of the nuclear factor-κB p65 subunit. Biochem. Pharmacol. 64:963–970.

    Google Scholar 

  53. Meyer, C.F., Wang, X., Chang, C., Templeton, D., and Tan, T.H. (1996). Interaction between c-Rel and the mitogen-activated protein kinase kinase 1 signaling cascade in mediating kappaB enhancer activation. J. Biol. Chem. 271:8971–8976.

    PubMed  CAS  Google Scholar 

  54. Sun, S.C., Maggirwar, S.B., and Harhaj, E. (1995). Activation of NF-kappa B by phosphatase inhibitors involves the phosphorylation of I kappa B alpha at phosphatase 2A-sensitive sites. J. Biol. Chem. 270:18347–18351.

    PubMed  CAS  Google Scholar 

  55. Chen, L.F., Mu, Y., and Greene, W.C. (2002). Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-kappaB. EMBO J. 21:6539–6548.

    PubMed  CAS  Google Scholar 

  56. Furia, B., Deng, L., Wu, K., et al. (2002). Enhancement of nuclear factor-kappa B acetylation by coactivator p300 and HIV-1 Tat proteins. J. Biol. Chem. 277:4973–4980.

    PubMed  CAS  Google Scholar 

  57. Kiernan, R., Bres, V., Ng, R.W., et al. (2003). Postactivation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65. J. Biol. Chem. 278: 2758–2766.

    PubMed  CAS  Google Scholar 

  58. Cogswell, J.P., Godlevski, M.M., Wisely, G.B., et al. (1994). NF-kappa B regulates IL-1 beta transcription through a consensus NF-kappa B binding site and a nonconsensus CRE-like site. J. Immunol. 153:712–723.

    PubMed  CAS  Google Scholar 

  59. McKay, L.I. and Cidlowski, J.A. (2000). CBP (CREB binding protein) integrates NF-kappaB (nuclear factor-kappaB) and glucocorticoid receptor physical interactions and antagonism. Mol. Endocrinol. 14:1222–1234.

    PubMed  CAS  Google Scholar 

  60. Ohmori, Y. and Hamilton, T.A. (1995). The interferon-stimulated response element and a kappa B site mediate synergistic induction of murine IP-10 gene transcription by IFN-gamma and TNF-alpha. J. Immunol. 154:5235–5244.

    PubMed  CAS  Google Scholar 

  61. Hassa, P.O. and Hottiger, M.O. (1999). A role of poly (ADP-ribose) polymerase in NF-kappaB transcriptional activation. Biol. Chem. 380:953–959.

    PubMed  CAS  Google Scholar 

  62. Oliver, F.J., Menissier-de Murcia, J., Nacci C., et al. (1999). Resistance to endotoxic shock as a consequence of defective NF-κB activation in poly (ADP-ribose) polymerase-1 deficient mice. EMBO J. 18:4446–4454.

    PubMed  CAS  Google Scholar 

  63. Shall, S. and de Murcia, G. (2000). Poly(ADP-ribose-polymerase-1: what have we learned from the deficient mouse model? Mutat. Res. 460:1–15.

    PubMed  CAS  Google Scholar 

  64. Lopez-Rodriguez, C., Aramburu, J., Jin, L., Rakeman, A.S., Michino, M., and Rao, A. (2001). Bridging the NFAT and NF-kappaB families: NFAT5 dimerization regulates cytokine gene transcription in response to osmotic stress. Immunity 15:47–58.

    PubMed  CAS  Google Scholar 

  65. Casolaro, V., Georas, S.N., Song, Z., et al. (1995). Inhibition of NF-AT-dependent transcription by NF-kappa B: implications for differential gene expression in T helper cell subsets. Proc. Natl. Acad. Sci. USA 92:11623–11627.

    PubMed  CAS  Google Scholar 

  66. Tsuboi, A., Muramatsu, M., Tsutsumi, A., Arai, K., and Arai, N. (1994). Calcineurin activates transcription from the GM-CSF promoter in synergy with either protein kinase C or NF-kappa B/AP-1 in T cells. Biochem. Biophys. Res. Commun. 199:1064–1072.

    PubMed  CAS  Google Scholar 

  67. Sica, A., Dorman, L., Viggiano, V., et al. (1997). Interaction of NF-kappaB and NFAT with the interferon-gamma promoter. J. Biol. Chem. 272:30412–30420.

    PubMed  CAS  Google Scholar 

  68. Bueno, O.F., De Windt, L.J., Tymitz, K.M., et al. (2000). The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO J. 19:6341–6350.

    PubMed  CAS  Google Scholar 

  69. Bueno, O.F., van Rooij, E., Molkentin, J.D., Doevendans, P.A., and De Windt, L.J. (2002a). Calcineurin and hypertrophic heart disease: novel insights and remaining questions. Cardiovasc. Res. 53:806–821.

    PubMed  CAS  Google Scholar 

  70. Molkentin, J.D., Lu, J.R., Antos, C.L., et al. (1998). A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93:215–228.

    PubMed  CAS  Google Scholar 

  71. Molkentin, J.D. (2000). Calcineurin and beyond: cardiac hypertrophic signaling. Circ. Res. 87:731–738.

    PubMed  CAS  Google Scholar 

  72. Frantz, B., Nordby, E.C., Bren, G., et al. (1994): Calcineurinacts in synergy with PMA to inactivate I kappa B/MAD3, an inhibitor of NF-kappa B. EMBO J. 13:861–870.

    PubMed  CAS  Google Scholar 

  73. Shumway, S.D., Berchtold, C.M., Gould, M.N., and Miyamoto, S. (2002). Evidence for unique calmodulin-dependent nuclear factor-kappaB regulation in WEHI-231 B cells. Mol. Pharmacol. 61:177–185.

    PubMed  CAS  Google Scholar 

  74. Steffan, N.M., Bren, G.D., Frantz, B., Tocci, M.J., O’Neill, E.A., and Paya, C.V. (1995). Regulation of IκB alpha phosphorylation by PKC- and Ca(2+)-dependent signal transduction pathways. J. Immunol. 155:4685–4691. PMID: 7594468.

    PubMed  CAS  Google Scholar 

  75. Pons, S. and Torres-Aleman, I. (2000). Insulin-like growth factor-I stimulates dephosphorylation of ikappa B through the serine phosphatase calcineurin (protein phosphatase 2B). J. Biol. Chem. 275:38620–38625.

    PubMed  CAS  Google Scholar 

  76. Trushin, S.A., Pennington, K.N., Algeciras-Schimnich, A., and Paya, C.V. (1999). Protein kinase C and calcineurin synergize to activate IkappaB kinase and NF-kappaB in T lymphocytes. J. Biol. Chem. 274:22923–22931.

    PubMed  CAS  Google Scholar 

  77. Biswas, G., Anandatheerthavarada, H.K., Zaidi, M., and Avadhani, N.G. (2003). Mitochondria to nucleus stress signaling: a distinctive mechanism of NF-κB/Rel activation through calcineurin-mediated inactivation of IκBα. J. Cell. Biol. 161:507–519.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  79. Chilov, D., Kukk, E., Taira, S., et al. (1997). Genomic organization of human and mouse genes for vascular endothelial growth factor C. J. Biol. Chem. 272:25176–25183.

    PubMed  CAS  Google Scholar 

  80. Collart, M.A., Baeuerle, P., and Vassalli, P. (1990): Regulation of tumor necrosis factor alpha transcription in macrophages: involvement of four kappa B-like motifs and of constitutive and inducible forms of NF-kappa B. Mol. Cell. Biol. 10:1498–1506.

    PubMed  CAS  Google Scholar 

  81. Hiscott, J., Marois, J., Garoufalis, J., et al. (1993). Characterization of a functional NF-kappa B site in the human interleukin 1 beta promoter: evidence for a positive autoregulatory loop. Mol. Cell. Biol. 13:6231–6240.

    PubMed  CAS  Google Scholar 

  82. Kinugawa, K., Shimizu, T., Yao, A., Kohmoto, O., Serizawa, T., and Takahashi, T. (1997). Transcriptional regulation of inducible nitric oxide synthase in cultured neonatal rat cardiac myocytes. Circ. Res. 81:911–921.

    PubMed  CAS  Google Scholar 

  83. Kishimoto, I., Rossi, K., and Garbers, D.L. (2001). A genetic model provides evidence that the receptor for atrial natriuretic peptide (guanylyl cyclase-A) inhibits cardiac ventricular myocyte. Proc. Natl. Acad. Sci. USA 98: 2703–2706.

    PubMed  CAS  Google Scholar 

  84. Pan, J. and McEver, R.P. (1995). Regulation of the human P-selectin promoter by Bcl-3 and specific homodimeric members of the NF-kappa B/Rel family. J. Biol. Chem. 270:23077–23083.

    PubMed  CAS  Google Scholar 

  85. Shakhov, A.N., Collart, M.A., Vassalli, P., Nedospasov, S.A., and Jongeneel, C.V. (1990). Kappa B-type enhancers are involved in lipopolysaccharide-mediated transcriptional activation of the tumor necrosis factor alpha gene in primary macrophages. J. Exp. Med. 171:35–47.

    PubMed  CAS  Google Scholar 

  86. Yamamoto, K., Arakawa, T., Ueda, N., and Yamamoto, S. (1995). Transcriptional roles of nuclear factor kappa B and nuclear factor-interleukin-6 in the tumor necrosis factor alpha-dependent induction of cyclooxy genase-2 in MC3T3-E1 cells. J. Biol. Chem. 270:31315–31320.

    PubMed  CAS  Google Scholar 

  87. Yin, L., Hubbard, A.K., and Giardina, C. (2002). NF-kappa B regulates transcription of the mouse telomerase catalytic subunit. J. Biol. Chem. 275:36671–36675.

    Google Scholar 

  88. Han, R., Ray, P., Baughman, K., and Feldman, A. (1991). Detection of interleukin and interleukin receptor mRNA in human heart by polymerase chain reaction. Biochem. Biophys. Res. Commun. 181:520–523.

    PubMed  CAS  Google Scholar 

  89. Matsumori, A., Yamada, T., Suzuki, H., Matoba, Y., and Sasayama, S. (1994). Increased circulating cytokines in patients with myocarditis and cardiomyopathy. Br. Heart J. 72:561–566.

    PubMed  CAS  Google Scholar 

  90. Satoh, M., Tamura, G., Segawa, I., Tashiro, A., Hiramori, K., and Satodate, R. (1996). Expression of cytokine genes and presence of enteroviral genomic RNA in endomyocardial biopsy tissues of myocarditis and cardiomyopathy. Virchows Arch. 427:503–509.

    PubMed  CAS  Google Scholar 

  91. Testa, M., Yeh, M., Lee, P., et al. (1996). Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension. J. Am. Coll. Cardiol. 28:964–971.

    PubMed  CAS  Google Scholar 

  92. Long, C.S. (2001). The role of interleukin-1 in the failing heart. Heart Fail. Rev. 6:81–94.

    PubMed  CAS  Google Scholar 

  93. Frangogiannis, N.G., Smith, C.W., and Entman, M.L. (2002). The inflammatory response in myocardial infarction. Cardiovasc. Res. 53:31–47.

    PubMed  CAS  Google Scholar 

  94. Kaminski, K.A., Bonda, T.A., Korecki, J., and Musial, W.J. (2002). Oxidative stress and neutrophil activation—the two keystones of ischemia/reperfusion injury. Int. J. Cardiol. 86:41–59.

    PubMed  Google Scholar 

  95. Kanda, T., Inoue, M., Kotajima, N., et al. (2000). Circulating interleukin-6 and interleukin-6 receptors in patients with acute and recent myocardial infarction. Cardiology 93:191–196.

    PubMed  CAS  Google Scholar 

  96. Neumann, F.J., Ott, I., Gawaz, M., et al. (1995). Cardiac release of cytokines and inflammatory responses in acute myocardial infarction. Circulation 92:748–755.

    PubMed  CAS  Google Scholar 

  97. Shibata, M., Endo, S., Inada, K., et al. (1997). Elevated plasma levels of interleukin-1 receptor antagonist and interleukin-10 in patients with acute myocardial infarction. J. Interferon Cytokine Res. 17:145–150.

    PubMed  CAS  Google Scholar 

  98. Mann, D.L. (1999). Cytokines as mediators of disease progression in the failing heart, in Congestive Heart Failure (J.D. Hosenpud and B.H. Greenberg, eds), Lippincott Williams & wilkins, Philadelphia, pp. 213–232.

    Google Scholar 

  99. Wollert, K.C. and Drexler, H. (2001). The role of interleukin-6 in the failing heart. Heart Failure Reviews 6: 95–103.

    PubMed  CAS  Google Scholar 

  100. Cain, B.S., Meldrum D.R., Dinarello, C.A., et al. (1999). Tumor necrosis factor-alpha and interleukin-1-beta synergistically depress human myocardial function. Crit. Care Med. 27:1309–1318.

    PubMed  CAS  Google Scholar 

  101. Panas, D., Khadow, F.H., Szabo, C., and Schultz, R. (1998). Proinflammatory cytokines depress cardiac efficiency by nitric oxide dependent mechanism. Am. J. Physiol. 275: H1016-H1023.

    PubMed  CAS  Google Scholar 

  102. Chandrasekar, B., Smith, J.B., and 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 

  103. Das, U.N. (2000)> Freeradicals, cytokines and nitric oxide in cardiac failure and myocardial infarction. Mol. Cell. Biochem. 215:145–152.

    PubMed  CAS  Google Scholar 

  104. Ono, K., Matsumori, A., Furukawa, Y., et al. (1999). Prevention of myocardial reperfusion injury in rats by an antibody against monocyte chemotactic and activating factor/monocyte chemoattractant protein-1. Lab. Invest. 79:195–203.

    PubMed  CAS  Google Scholar 

  105. Bauriedel, G., Hutter, R., Welsch, U., Bach, R., Sievert, H., and Luderitz, B. (1999). Role of smooth muscle cell death in advanced coronary primary lesions: implications for plaque instability. Cardiovasc. Res. 41:480–488.

    PubMed  CAS  Google Scholar 

  106. Breuss, J.M., Cejna, M., Bergmeister, H., et al. (2002). Activation of nuclear factor-kappa B significantly contributes to lumen loss in a rabbit iliac artery balloon angioplasty model. Circulation 105:633–638.

    PubMed  CAS  Google Scholar 

  107. Cooper, M., Lindholm, P., Peiper, G., et al. (1998). Myocardial nuclear factor-κB activity and nitric oxide production in rejecting cardiac allografts. Transplantation 66:838–844.

    PubMed  CAS  Google Scholar 

  108. Ritchie, M.E. (1998). Nuclear factor-κB is selectively and markedly activated in humans with unstable angina pectoris. Circulation 98:1707–1713.

    PubMed  CAS  Google Scholar 

  109. Valen, G., Hansson, G.K., Dumitrescu, A., and Vaage, J. (2000). Unstable angina activates myocardial heat shock protein 72, endothelial nitric oxide synthase, and transcription factors NFkappaB and AP-1. Cardiovasc. Res. 47:49–56.

    PubMed  CAS  Google Scholar 

  110. Kubota, T., McTiernan, C.F., Frye, C.S., et al. (1997). Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ. Res. 81:627–635.

    PubMed  CAS  Google Scholar 

  111. Morgan, E.N., Boyle, E.M., Jr., Yun, W., et al. (1999) An essential role for NF-kappaB in the cardioadaptive response to ischemia. Ann. Thorac. Surg. 68:377–382.

    PubMed  CAS  Google Scholar 

  112. Xuan, Y.T., Tang, X.L., Banerjee, S., et al. (1999). Nuclear factor-kappaB plays an essential role in the late phase of ischemic preconditioning in conscious rabbits. Circ. Res. 84:1095–1109.

    PubMed  CAS  Google Scholar 

  113. Zhao, T.C. and Kukreja, R.C. (2002). Related Articles, Links Abstract Late preconditioning elicited by activation of adenosine A(3) receptor in heart: role of NF-kappa B, iNOS and mitochondrial K(ATP) channel. J. Mol. Cell. Cardiol. 34:263–277.

    PubMed  CAS  Google Scholar 

  114. Canty, T.G., Jr., Boyle, E.M., Jr., Farr, A., Morgan, E.N., Verrier, E.D., and Pohlman, T.H. (1999). Oxidative stress induces NF-kappaB nuclear translocation without degradation of IkappaBalpha. Circulation 100(19 Suppl II): 361–364.

    CAS  Google Scholar 

  115. Maulik, N., Sasaki, H., Addya, S., and Das, D.K. (2000). Regulation of cardiomyocyte apoptosis by redox-sensitive transcription factors. FEBS Lett. 485:7–12.

    PubMed  CAS  Google Scholar 

  116. Sasaki, H., Galang, N., and Maulik, N. (1999). Redox regulation of NF-kappaB and AP-1 in ischemic reperfused heart. Antioxid. Redox Signal 1:317–324.

    PubMed  CAS  Google Scholar 

  117. Wong, S.C., Fukuchi, M., Melnyk, P., Rodger, I., and Giaid, A. (1998). Induction of cyclooxygenase-2 and activation of NF-κB in myocardium of patients with congestive heart failure. Circulation 98:100–103.

    PubMed  CAS  Google Scholar 

  118. Gupta, S. and Sen, S. (2002). Myotrophin-kappaB DNA interaction in the initiation process of cardiac hypertrophy. Biochim. Biophys. Acta 1589:247–260.

    PubMed  CAS  Google Scholar 

  119. Higuchi, Y., Otsu, K., Nishida, K., et al. (2002). Involvement of reactive oxygen species-mediated NF-kappa B activation in TNF-alpha-induced cardiomyocyte hypertrophy. J. Mol. Cell. Cardiol. 34:233–240.

    PubMed  CAS  Google Scholar 

  120. Purcell, N.H., Tang, G., Yu, C., Mercurio, F., DiDonato, J.A., and Lin, A. (2001). Activation of NF-κB is required for hypertrophic growth of primary rat neonatal ventricular cardiomyocytes. PNAS 98:6668–6673.

    PubMed  CAS  Google Scholar 

  121. Bryant, D., Becker, L., Richardson, J., et al. (1998). Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. Circulation 97:1375–1381.

    PubMed  CAS  Google Scholar 

  122. Sivasubramanian, N., Coker, M.L., Kurrelmeyer, K.M. et al. (2001). Left ventricular remodeling in transgenic mice with cardiac restricted overexpression of tumor necrosis factor. Circulation 104:826–831.

    PubMed  CAS  Google Scholar 

  123. Baumgarten, G., Knuefermann, P., Kalra, D., et al. (2002). Load-dependent and-independent regulation of proin flammatory cytokine and cytokine receptor gene expression in the adultmammalian heart. Circulation 105:2192–2197.

    PubMed  CAS  Google Scholar 

  124. De Keulenaer, G.W., Wang, Y., Feng, Y., et al. (2002). Identification of IEX-1 as a biomechanically controlled nuclear factor-kappaB target gene that inhibits cardiomyocyte hypertrophy. Circ. Res. 90:690–696.

    PubMed  Google Scholar 

  125. Liang, F. and Gardner, D.G. (1999). Mechanical strain activates BNP gene transcription through a p38/NF-kappaB-dependent mechanism. J. Clin. Invest. 104:1603–1612.

    PubMed  CAS  Google Scholar 

  126. Saganek, L.J., Ignasiak, D.P., Batley, B.L., Potoczak, R.E., Dodd, G., and Gallagher, K.P. (1997). Heat stress increases cardiac HSP72i but fails to reduce myocardial infarct size in rabbits 24 hours later. Basic Res. Cardiol. 92:331–338.

    PubMed  CAS  Google Scholar 

  127. Carlson, D.L., White, D.J., Maass, D.L., Nguyen, R.C., Giroir B., and Horton, J.W. (2003). Ikappa B overexpression in cardiomyocytes prevents NF-kappa B translocation and provides cardioprotection in trauma. Am. J. Physiol. Heart Circ. Physiol. 284:H804-H814.

    PubMed  CAS  Google Scholar 

  128. Maass, D.L., Hybki, D.P., White, J., and Horton, J.W. (2002). The time course of cardiac NF-kappaB activation and TNF-alpha secretion by cardiac myocytes after burn injury: contribution toburn-related cardiac contractile dysfunction. Shock 17:293–299.

    PubMed  Google Scholar 

  129. Bergmann, M.W., Loser, P., Dietz, R., and von Harsdorf, R. (2001). Effect of NF-kappa B Inhibition on TNF-alpha-induced apoptosis and downstream path ways in cardiomyocytes. J. Mol. Cell. Cardiol. 33:1223–1232.

    PubMed  CAS  Google Scholar 

  130. Cowling, R.T., Gurantz, D., Peng, J., Dillmann, W.H., and Greenberg, B.H. (2002). Transcription factor NF-kappaB is necessary for up-regulation of type 1 angiotensin II receptor mRNA in rat cardiac fibroblasts treated with tumor necrosis factor-alpha or interleukin-1 beta. J. Biol. Chem. 277:5719–5724.

    PubMed  CAS  Google Scholar 

  131. Wang, S., Kotamraju, S., Konorev, E., Kalivendi, S., Joseph, J., and Kalyanaraman, B. (2002). Activation of nuclear factor-kappaB during doxorubicin-induced apoptosis in endothelial cells and myocytes is pro-apoptotic: the role of hydrogen peroxide. Biochem. J. 367:729–740.

    PubMed  CAS  Google Scholar 

  132. Wei, Z., Costa, K., Al-Mehdi, A.B., Dodia, C., Muzykantov, V., and Fisher, A.B. (1999). Simulated ischemia in flow-adapted endothelial cells leads to generation of reactive oxygen species and cell signaling. Circ. Res. 85: 682–689.

    PubMed  CAS  Google Scholar 

  133. Bourcier, T., Sukhova, G., and Libby, P. (1997). The nuclear factor-κB signaling pathway participates in dysregulation of vascular smooth muscle cells in vitro and in human atherosclerosis. JBC 272:15817–15824.

    CAS  Google Scholar 

  134. Brand, K., Page, S., Rogler, G., et al. (1996). Activated nuclear factor-κB in present in the atherosclerotic lesion. JCI 97:1715–1722.

    PubMed  CAS  Google Scholar 

  135. Bellas, R.E., Lee, J.S., and Sonenshein, G.E. (1995). Expression of a constitutive NF-kappa B-like activity is essential for proliferation of cultured bovine vascular smooth muscle cells. J. Clin. Invest. 96:2521–2527.

    PubMed  CAS  Google Scholar 

  136. Autieri, M.V., Yue, T.L., Ferstein, G.Z., and Ohlstein, E. (1995). Antisense oligonucleotides to the p65 subunit of NF-κB inhibit human vascular smooth muscle cell adherence and proliferation and prevent neointima formation in rat carotid arteries. Biochem. Biophys. Res. Commun. 213:827–836.

    PubMed  CAS  Google Scholar 

  137. Berliner, J.A., Navab, M., Fogelman, A.M., et al. (1995). Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation 91:2488–2496.

    PubMed  CAS  Google Scholar 

  138. Erl, W., Hansson, G.K., de Martin, R., Draude, G., Weber, K.S., and Weber, C. (1999). Nuclear factor-kappa B regulates induction of apoptosis and inhibitor of apoptosis protein-1 expression in vascular smooth muscle cells. Circ. Res. 84:668–677.

    PubMed  CAS  Google Scholar 

  139. Hayashi, K., Takahata, H., Kitagawa, N., Kitange, G., Kaminogo, M., and Shibata, S. (2001). N-acetylcysteine inhibited nuclear factor-kappaB expression and the intimal hyperplasia in rat carotid arterial injury. Neurol. Res. 23:731–738.

    PubMed  CAS  Google Scholar 

  140. Ortego, M., Bustos, C., Hernandez-Presa, M.A., et al. (1999). Atorvastatin reduces NF-kappaB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells. Atherosclerosis 147:253–261.

    PubMed  CAS  Google Scholar 

  141. Matsui, H., Ihara, Y., Fujio, Y., et al. (1999). Induction of interleukin (IL)-6 by hypoxia is mediated by nuclear factor (NF)-kappa B and NF-IL6 in cardiac myocytes. Cardiovasc. Res. 42:104–112.

    PubMed  CAS  Google Scholar 

  142. Peng, M., Huang, L., Xie, Z.J., Huang, W.H., and Askari, A. (1995). Oxidant-induced activations of nuclear factor-kappaB and activator protein-1 in cardiac myocytes. Cell. Mol. Biol. Res. 41:189–197.

    PubMed  CAS  Google Scholar 

  143. Fisher, A.B., Al-Mehdi, A.B., and Manevich, Y., (2002). Shear stress and endothelial cell activation. Crit. Care Med. 30(5 Suppl):S192-S197.

    PubMed  CAS  Google Scholar 

  144. McGuinness, M., Brown, M., Wright, T., et al. (2003). Transdominant blockade of NF-κB in cardiac pathophysiology. Submitted.

  145. Gupta, S., Purcell, N.H., Lin, A., and Sen, S. (2002). Activation of nuclear factor-κB is necessary for myotrophin-induced cardiac hypertrophy. J. Cell Biol. 159: 1019–1028.

    PubMed  CAS  Google Scholar 

  146. Anderson, K.M., Berrebi-Bertrand, I., Kirkpatrick, R.B., et al. (1999). cDNA sequence and characterization of the gene that encodes human myotrophin/V-1 protein, a mediator of cardiac hypertrophy. J. Mol. Cell. Cardiol. 31: 705–719.

    PubMed  CAS  Google Scholar 

  147. Sivasubramanian, N., Adhikary, G., Sil, P.C., and Sen, S. (1996). Cardiac myotrophin exhibits rel/NF-kappa B interacting activity in vitro. J. Biol. Chem. 271:2812–2816.

    PubMed  CAS  Google Scholar 

  148. Sil, P., Misono, K., and Sen, S. (1993). Myotrophin in human cardiomyopathic heart. Circ. Res. 73:98–108.

    PubMed  CAS  Google Scholar 

  149. Sen, S., Kundu, G., Mekhail, N., Castel, J., Misono, K., and Healy, B. (1990). Myotrophin: purification of a novel peptide from spontaneously hypertensive rat heart that influences myocardial growth. J. Biol. Chem. 265:16635–16643.

    PubMed  CAS  Google Scholar 

  150. Grabellus, F., Lavkau, B., Sokoll, A., et al. (2002). Reversible activation of nuclear factor-kappa B in human end-stage heart failure after left ventricular mechanical support. Cardiovasc. Res. 53:124–130.

    PubMed  CAS  Google Scholar 

  151. Saito, T. and Giaid, A. (1999). Cyclooxygenase-2 and nuclear factor-kappaB in myocardium of end stage human heart failure. Congest. Heart Fail. 5:222–227.

    PubMed  CAS  Google Scholar 

  152. Wang, W., Tam, W.F., Hughes, C.C., Rath, S., and Sen, R. (1997). c-Rel is a target of pentoxifylline-mediated inhibition of T lymphocyte activation. Immunity 6:165–174.

    PubMed  CAS  Google Scholar 

  153. Sliwa, K., Skudicky, D., Candy, G., Wisenbaugh, T., and Sareli, P. (1998). Randomized investigation of effects of pentoxlflline on left ventricular performance in idiopathic dilated cardiomyopathy. Lancet 351:1091–1093.

    PubMed  CAS  Google Scholar 

  154. Jimenez, J.L., Punzon, C., Navarro, J., Munoz-Fernandez, M.A., and Fresno, M. (2001). Phosphodiesterase 4 inhibitors prevent cytokine secretion by T lymphocytes by inhibiting nuclear factor-kappaB and nuclear factor of activated T cells activation. J. Pharmacol. Exp. Ther. 299:753–759.

    PubMed  CAS  Google Scholar 

  155. Majumdar, S., Lamothe, B., and Aggarwal, B.B. (2002). Thalidomide suppresses NF-kappa B activation induced by TNF and H2O2, but not that activated by ceramide, lipopolysaccharides, or phorbol ester, J. Immunol. 168: 2644–2651.

    PubMed  CAS  Google Scholar 

  156. Kondratyev, A.D., Chung, K.N., and Jung, M.O. (1996). Identification and characterization of a radiation-inducible glycosylated human early-response gene. Cancer Res. 56:1498–1502.

    PubMed  CAS  Google Scholar 

  157. Ohki, R., Yamamoto, K., Mano, H., Lee, R.T., Ikeda, U., and Shimada, K. (2002). Identification of mechanically induced genes in human monocytic cells by DNA microarrays. J. Hypertens. 20:685–691.

    PubMed  CAS  Google Scholar 

  158. Garcia, J., Ye, Y., Arranz, V., Letourneux, C., Pezeron, G., and Porteu, F. (2002). IEX-1: a new ERK substrate involved in both ERK survival activity and ERK activation. EMBO J. 21:5151–5163.

    PubMed  CAS  Google Scholar 

  159. Izumi, T., Saito, Y., Kishimoto, I., et al. (2001). Blockade of the natriuretic peptide receptor guanylyl cyclase-A inhibits NF-kappaB activation and alleviates myocardial ischemia/reperfusion injury. J. Clin. Invest. 108: 203–213.

    PubMed  CAS  Google Scholar 

  160. Kiemer, A.K., Weber, N.C., and Vollmar, A.M. (2002). Induction of IkappaB: atrial natriuretic peptide as a regulator of the NF-kappaB, pathway. Biochem. Biophys. Res. Commun. 295:1068–1076.

    PubMed  CAS  Google Scholar 

  161. Kadokami, T., Frye, C., Lemster, B., Wagner, C., Feldman, A., and McTiernan, C. (2001). Anti-tumor necrosis factor-alpha antibody limits heart failure in a transgenic model. Circulation 104:1094–1097.

    PubMed  CAS  Google Scholar 

  162. Kubota, T., Bounoutas, G.S., Miyagishima, M., et al. (2000). Soluble tumor necrosis factor receptor abrogates myocardial inflammation but not hypertrophy in cytokine-induced cardiomyopathy. Circulation 101:2518–2525.

    PubMed  CAS  Google Scholar 

  163. Li, Y.Y., Feng, Y.Q., Kadokami, T., et al. (2000). Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by tumor necrosis factor alpha therapy. Proc. Natl. Acad. Sci. USA 97:12746–12751.

    PubMed  CAS  Google Scholar 

  164. Li, Y.Y., Kadokami, T., Wang, P., McTiernan, C.F., and Feldman, A.M. (2002). MMP inhibition modulates TNF-alpha transgenic mouse phenotype early in the development of heart failure. Am. J. Physiol. Heart. Circ. Physiol. 282: H983-H989.

    PubMed  CAS  Google Scholar 

  165. Funakoshi, H., Kubota, T., Machita, Y., et al. (2002). Disruption of inducible nitric oxide synthase improves beta-adrenergic inotropic responsiveness but not the survival of mice with cytokine-induced cardiomyopathy. Circ. Res. 90:959–965.

    PubMed  CAS  Google Scholar 

  166. Funakosh, I.H., Kubota, T., Machita, Y., et al. (2002a). Involvement of inducible nitric oxide synthase in cardiac dysfunction with tumor necrosis factor-α. Am. J. Physiol. Heart. 282, H2159-H2166.

    Google Scholar 

  167. Kaye, D.M., Wiviott, S.D., and Kelly, R.A. (1999). Activation of nitric oxide synthase (NOS3) by mechanical activity alters mechanical contractile activity in a Ca+2-independent manner in cardiac myocytes: role of troponin I phosphorylation. Biochem. Biophys. Res. Commun. 256:398–403.

    PubMed  CAS  Google Scholar 

  168. Tavernier, B., Li, J.M., El-Omar, M.M., et al. (2001). Cardiac contractile impairment associated with increased phosphorylation of troponin I in endotoxemic rats. FASEB J. 15:294–296.

    PubMed  CAS  Google Scholar 

  169. Hirota, H., Chen, J., Betz, U.A., et al. (1999)., Loss of a gp 130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell 97:189–198.

    PubMed  CAS  Google Scholar 

  170. Kunisada, K., Tone, E., Fujio, Y., Matsui, H., Yamauchi-Takihara, K., and Kishimoto, T. (1998). Activation of gp 130 transduces hypertrophic signals via STAT3 in cardiac myocytes. Circulation 98:346–352.

    PubMed  CAS  Google Scholar 

  171. Matsui, H., Fujio, Y., Kunisada, K., Hirota, H., and Yamauchi-Takihara, K. (1996). Leukemia inhibitory factor induces a hypertrophic response mediated by gp 130 in murine cardiac myocytes. Res. Commun. Mol. Pathol. Pharmacol. 93:149–162.

    PubMed  CAS  Google Scholar 

  172. Brasier, A.R., Jamaluddin, M., Han, Y., Patterson, C., and Runge, M.S. (2000). Angiotensin II induces gene transcription through cell-type-dependent effects on the nuclear factor-kappaB (NF-kappaB) transcription factor. Mol. Cell. Biochem. 212:155–169.

    PubMed  CAS  Google Scholar 

  173. Rouet-Benzineb, P., Gontero, B., Dreyfus, P., and Lafuma, C. (2000). Angiotensin II induces nuclear factor-kappa B activation in cultured neonatal rat cardiomyocytes through protein kinase C signaling pathway. J. Mol. Cell. Cardiol. 32:1767–1778.

    PubMed  CAS  Google Scholar 

  174. Bueno, O.F. and Molkentin, J.D. (2002). Involvement of extracellular signal-regulated kinases 1/2 in cardiac hypertrophy and cell death. Circ. Res. 91:776–781.

    PubMed  CAS  Google Scholar 

  175. Abbate, A., Biondi-Zoccai, G.G., and Baldi, A. (2002). Pathophysiologic role of myocardial apoptosis in post-infarction left ventricular remodeling. J. Cell. Physiol. 193:145–153.

    PubMed  CAS  Google Scholar 

  176. Kumar, D., Lou, H., and Singal, P.K. (2002). Oxidative stress and apoptosis in heart dysfunction. Herz 27:662–668.

    PubMed  Google Scholar 

  177. Tomei, L.D. and Umansky, S.R. (2001). Apoptosis and the heart: a brief review. Ann. NY Acad. Sci. 946:160–168.

    PubMed  CAS  Google Scholar 

  178. Wernig, F. and Xu, Q. (2002). Mechanical stress-induced apoptosis in the cardiovascular system. Prog. Biophys. Mol. Biol. 78:105–137.

    PubMed  CAS  Google Scholar 

  179. Bernecker, O.Y., Huq, F., Heist, E.K., Podesser, B.K., and Haijar, R.J. (2003). Apoptosis in heart failure and the senescent heart. Cardiovasc. Toxicol. 3:183–190.

    PubMed  CAS  Google Scholar 

  180. McGowan, B.S., Ciccimaro, E.F., Chan, T.O., and Feldman, A.M. (2003). The balance between pro-apoptotic and antiapoptotic pathways in the failing myocardium. Cardiovasc. Toxicol. 3:191–206.

    PubMed  CAS  Google Scholar 

  181. Clerk, A., Cole, S.M., Cullingford, T.E., Harrison, J.G., Jormakka, M., and Valks, D.M. (2003). Regulation of cardiac myocyte cell death. Pharm. Ther. 97:223–261.

    CAS  Google Scholar 

  182. Leri, A., Claudio, P.P., Li, Q., et al. (1998). Stretchmediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell. J. Clin. Invest. 101:1326–1342.

    PubMed  CAS  Google Scholar 

  183. Yussman, M.G., Toyokawa, T., Odley, A., et al. (2002). Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy. Nat. Med. 8:725–730.

    PubMed  CAS  Google Scholar 

  184. Nadal-Ginard, B., Kajstura, J., Leri, A., and Anversa, P. (2003). Myocyte death, growth, and regeneration in cardiac hypertrophy and failure. Circ. Res. 92:139–150.

    PubMed  CAS  Google Scholar 

  185. Canicio, J., Ruiz-Lozano, P., Carrasco, M., et al. (2001). Nuclear factor kappa B-inducing kinase and Ikappa B kinase-alpha signal skeletal muscle cell differentiation. J. Biol. Chem. 276:20228–20233.

    PubMed  CAS  Google Scholar 

  186. Conejo, R., Valverde, A.M., Benito, M., and Lorenzo, M. (2001). Insulin produces myogenesis in C2C12 myoblasts by induction of NF-kappaB and downregulation of AP-1 activities. J. Cell Physiol. 186:82–94.

    PubMed  CAS  Google Scholar 

  187. Li, Y.P. and Reid, M.B. (2000). NF-kappaB mediates the protein loss induced by TNF-alpha in differentiated skeletal mucle myotubes. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279:R1165-R1170.

    PubMed  CAS  Google Scholar 

  188. Thaloor, D., Miller, K.J., Gephart, J., Mitchell, P.O., and Pavlath, G.K. (1999). Systemic administration of the NFkappaB inhibitor curcumin stimulates muscle regeneration after traumatic injury. Am. J. Physiol. 277:C320-C329.

    PubMed  CAS  Google Scholar 

  189. Guttridge, D.C., Mayo, M.W., Madrid, L.V., Wang, C.Y., and Baldwin, A.S. Jr. (2000). NF-kappaB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science 289:2363–2366.

    PubMed  CAS  Google Scholar 

  190. Shintani, T., Sawa, Y., Takahashi T., et al. (2002). Intraoperative transfection of vein grafts with the NFkappaB decoy in a canine aortocoronary bypass model: a strategy to attenuate intimal hyperplasia. Ann. Thorac. Surg. 74: 1132–1137; discussion 1137–1138.

    PubMed  Google Scholar 

  191. Misra, A., Chen, Z., Sivasubramanian, N. et al. (2001). Both cardiac myocyte apoptosis and infarct size are increased in mice with defective NF-κB signaling. Circulation 104(Suppl.):II-11.

    Google Scholar 

  192. Bolli, R., Shinmura, K., Tang, X.L. et al. (2002). Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning. Cardiovasc. Res. 55:506–519.

    PubMed  CAS  Google Scholar 

  193. Li, C., Browder, W., and Kao, R.L. (1999). Early activation of transcription factor NF-kappaB during ischemia in perfused rat heart. Am. J. Physiol. 276:H543-H552.

    PubMed  CAS  Google Scholar 

  194. Balligand, J.L., Ungureanu-Longrois, D., Simmons, W.W., et al., (1994). Cytokine-inducible nitric oxide synthase (iNOS) expresion in cardiac myocytes. Characterization and regulation of iNOS expression and detection of iNOS activity in single cardiac myocytes in vitro. J. Biol. Chem. 269:L27580–27588.

    Google Scholar 

  195. Zhang, D., Jiang, S.L., Rzewnicki, D., Samols, D., and Kushner, I. (1995). The effect of interleukin-1 on C-reactive protein expression in Hep3B cells is exerted at the transcriptional level. Biochem. J. 310:143–148.

    PubMed  CAS  Google Scholar 

  196. Maulik, N., Goswami, S., Galang N., and Das, D.K. (1999). Differential regulation of Bcl-2, AP-1 and NFkappaB on cardiomyocyte apoptosis during myocardial ischemic stress adaptation. FEBS Lett. 443;331–336.

    PubMed  CAS  Google Scholar 

  197. Mustapha, S., Kirshner, A., De Moissac, D., and Kirshenbaum, L.A. (2000). A direct requirement of nuclear factor-kappa B for suppression of apoptosis in ventricular myocytes. Am. J. Physiol. Heart Circ. Physiol. 279: H939-H945.

    PubMed  CAS  Google Scholar 

  198. Irem, S.O., Eyer, C.L., Smith, J.R., and Anderson, A.C., (1991). Protective effects of selected sulfhydryl containing compounds against global ischemia in isolated perfused rat hearts. Proc. West Pharmacol. Soc. 34:161–165.

    PubMed  CAS  Google Scholar 

  199. Biagnini, G., Sala, D., and Zini, I. (1995). Diethyldithioncabamate, a superoxide dismutase inhibitor, counteracts the maturation of ischemic-like lesions caused by endothelin-1 intrastriatal injection. Neurosci. Lett. 190:212–216.

    Google Scholar 

  200. Sawa, Y., Morishita, R., Suzuki, K., et al. (1997). A novel strategy for myocardial protection using in vivo transfection of cis element ’decoy’ against NFkappaB binding site: evidence for a role of NFkappaB in ischemia-reperfusion injury. Circulation 96(9 Suppl II):280–284.

    CAS  Google Scholar 

  201. Morishita, R., Sugimoto, T., Aoki, M., et al. (1997). Invivo transfection of cis element “decoy” against nuclear factor-kappaB binding siteprevents myocardial infarction. Nat. Med. 3:894–899.

    PubMed  CAS  Google Scholar 

  202. Saito, T., Rodger, I.W., Shennib, H., Hu, F., Tayara, L., and Giaid, A. (2003). Cyclooxygenase-2 (COX-2) in acute myocardial infarction: cellular expression and use of selective COX-2 inhibitor. Can. J. Physiol. Pharmacol. 81:114–119.

    PubMed  CAS  Google Scholar 

  203. Hocherl, K., Dreher, F., Kurtz, A., and Bucher, M. (2002). Cyclooxygenase-2 inhibition attenuates lipopolysaccharide-induced cardiovascular failure. Hypertension 40:947–953.

    PubMed  Google Scholar 

  204. Kurrelmeyer, K.M., Michael, L.H., Baumgarten, G., et al. (2000). Endogenous tumor necrosis factor protects the adult cardiac myocyte againstischemic-induced apoptosis in a murine model of acute myocardial infarction. PNAS 99:5456–5461.

    Google Scholar 

  205. Maekawa, N., Wada, H., Kanda, T., et al. (2002). Improved proved myocardial ischemia/reperfusion injury in mice lacking tumor necrosis factor-alpha. J. Am. Coll. Cardiol. 39:1229–1235.

    PubMed  CAS  Google Scholar 

  206. Kajstura, J., Cheng, W., Reiss, K., et al. (1996). Apoptotic and necrotic myocyte cell deaths are independent comtributing variables of infarct size in rats. Lab. invest. 74:86–107.

    PubMed  CAS  Google Scholar 

  207. Gustafsson, A.B., Sayen, M.R., Williams, S.D., Crow, M.T., and Gottlieb, R.A. (2002). TAT protein transduction into isolated perfused hearts: TAT-apoptosis represor with caspase recruitment domain is carioprotective. Circulation 106:735–739.

    PubMed  CAS  Google Scholar 

  208. Halestrap, A.P. (1999). The mitochondrial permeability transition: its molecular mechanisms and role in reperfusion injury. Biochem. Soc. Symp. 66:181–203.

    PubMed  CAS  Google Scholar 

  209. Pacher, P., Csordas, G. and Hajnoczky, G. (2001). Mitochondrial Ca(2+) signaling and cardiac apoptosis. Biol. Signals Recept. 10:200–223.

    PubMed  CAS  Google Scholar 

  210. Meldrum, D.R., Cleveland, J.C. Jr., Sheridan, B.C., et al.. (1997). Alpha-adrenergic activation of myocardial NFkappaB during hemorrhage. J. Surg. Res. 69:268–276.

    PubMed  CAS  Google Scholar 

  211. Hiasa, G., Hamada, M., Ikeda, S., and Hiwada, K. (2001). Ischemic preconditioning and lipopolysaccharide attenuate nuclear factor-kappaB activation and gene expression of inflammatorycytokines in the ischemia-reperfused rat heart. Jpn. Circ. J. 65:984–990.

    PubMed  CAS  Google Scholar 

  212. Kim, H. and Koh G. (2000). Lipopolysaccharide activates matrix metalloproteinase-2 in endothelial cells through an NF-kappaB-dependent pathway. Biochem. Biophys. Res. Commun. 269:401–405.

    PubMed  CAS  Google Scholar 

  213. Lakshminarayanan, V., Lewallen, M., Frangogiannis, N.G., et al. (2001). Reactive oxygen in termediates induced monocyte chemotactic protein-1 in vascular endothelium after brief ischemia. Am. J. Pathol. 159:1301–1311.

    PubMed  CAS  Google Scholar 

  214. Sasaki, H., Fukura, S., Otani, H., et al. (2002). Hypoxic preconditioning triggers myocardial angiogenesis: a novel approach to enhance contractile functional reserve in rat with my ocardial infarction. J. Mol. Cell. Cardiol. 34: 335–348.

    PubMed  CAS  Google Scholar 

  215. Maulik, N., and Das, D.K. (2002). Potentiation of angiogenic response by ischemic and hypoxic preconditioning of the heart. J. Cell. Mol. Med. 6:13–24.

    PubMed  CAS  Google Scholar 

  216. Delogu G., Signore, M., Mechelli, A. and Famularo, G. (2002). Heat shock proteins and their role in heart injury. Curr. Opin. Crit. Care 8:411–416.

    PubMed  Google Scholar 

  217. Dillnamm, W.H., (1999). Small heat shock proteins and protection against injury. Ann. NY Acd. Sci. 874:66–68.

    Google Scholar 

  218. Dillmann, W.H. (1999). Heat shock proteins and protection against ischemic injury. Infect. Dis. Obstet. Gynecol. 7:55–57.

    CAS  Google Scholar 

  219. Latchman, D.S. (2001). Heat shock proteins and cardiac protection. Cardiovasc. Res. 51:637–646.

    PubMed  CAS  Google Scholar 

  220. Knowlton, A.A. and Gupta, S. (2003). HSP60, Bax and cardiac apoptosis. Cardiovasc. Toxicol. 3:263–268.

    PubMed  CAS  Google Scholar 

  221. Dobbin, C.A., Smith, N.C, and Johson, A.M. (2002). Heat shock protein 70 is a potential virulence factor in murine toxoplasma infection via immunomodulation of host NF-κB and nitric oxide. J. Immunol. 169:958–965.

    PubMed  CAS  Google Scholar 

  222. Heimbach, J.K., Reznikov, L.L., Calkins, C.M., et al. (2001). TNF receptor I is required for induction of macrophage heat shock protein 70. Am. J. Physiol. Cell Pohysiol. 281:C241-C247.

    CAS  Google Scholar 

  223. Kim, Y.M., de Vera, M.E., Watkins, S.C., and Billiar, T.R. (1997). Nitric oxide protects cultured rat hepatocytes from tumor necrosis factor-alpha-induced apoptosis by inducing heat shock protein 70 expression. J. Biol. Chem. 272:1402–1411.

    PubMed  CAS  Google Scholar 

  224. Meng, X. and Harken, A.H. (2002). The interaction between Hsp70 and TNF-alpha expression: a novel mechanism for protection of the myocardium against post-injury depression. Shock 17:345–353.

    PubMed  Google Scholar 

  225. Malhotra, V. and Wong, H.R. (2002). Interactions between the heat shock response and the nuclear factor-kappaB signaling pathway. Crit. Care Med. 30(1Suppl):S89-S95.

    CAS  Google Scholar 

  226. Guzhova, I.V., Darieva, Z.A., Melo, A.R., and Margulis B.A. (1997). Major stress protein Hsp 70 interacts with NF-κB regulatory complex in human T-lymphoma cells. Cell Stress Chaperones 2:132–139.

    PubMed  CAS  Google Scholar 

  227. Nayeem, M.A., Elliott, G.T., Shah, M.R., Hastillo-Hess, S.L., and Kukreja, R.C. (1997a). Monophosphoryl lipid A protects adult rat cardiac myocytes with the induction of the 72kD heat shock protein: a cellular model of pharmacologic preconditioning. JMCC 29:2305–2310.

    CAS  Google Scholar 

  228. Nayeem, M.A., Hess, M.L., Qian, Y.Z., Loesser, K.E., and Kukreja, R.C. (1997b). Delayed preconditioning of cultured rat cardiac myocytes: role of 70- and 90- kDa heats shock proteins. Am. J. Physiol. 273:H861-H868.

    PubMed  CAS  Google Scholar 

  229. Chong, K.Y., Lai, C.C., Lille, S., Chang, C., and Su, C.Y. (1998). Stable overex pression of the consitutive form of heat shock protein 70 confers oxidative protection. JMCCC 30:599–608.

    CAS  Google Scholar 

  230. Miller, M.J. (2001). Preconditioning for cardioprotection against ischemia reperfusion injury: the roles of nitric oxide, reactive oxygen species, heat shock proteins, reactive hyperemia and antioxidants—a mini review. Can. J. Cardiol. 17:1075–1082.

    PubMed  CAS  Google Scholar 

  231. Qian, Y.Z., Bernardo, N.I., Nayeem, M.A., Chelliah, J., and Kukreja, R.C. (1999) Induction of the 72 kDa heat shock protein does not produce the second window of ischemic preconditioning in rat heart. Am. J. Physiol. 276: H224-H234.

    PubMed  CAS  Google Scholar 

  232. Lee, S.H., Kim, M., Yoon, B.W., et al. (2001). Targeted Hsp 70.1 disruption increases infarction volume after focal cerebral ischemia in mice. Stroke 32:2905–2912.

    PubMed  CAS  Google Scholar 

  233. Gottdiener, J.S., Arnold, A.M., Aurigemma, G.P., et al.. (2000). Predictors of congestive heart failure in the elderly: the Cardiovascular Health Study. J. Am. Coll. Cardiol. 35:1628–1637.

    PubMed  CAS  Google Scholar 

  234. Hayward, C.S., Kelly, R.P., and Collins, P. (2000). The roles of gender, the menopause and hormone replacement on cardiovascular function. Cardiovasc. Res. 46:28–49.

    PubMed  CAS  Google Scholar 

  235. Stampfer, M.J. and Coditz, G.A. (1991) Estrogen replacement therapy and coronary heart disese: a quantitative assessment of the epidemiologic evidence. Prev. Med. 20: 47–63.

    PubMed  CAS  Google Scholar 

  236. Mendelsohn, M.E. (2000). Mechanisms of estrogen action in the cardiovascular system. J. Steroid Biochem. Mol. Biol. 74:337–343.

    PubMed  CAS  Google Scholar 

  237. Johnson, B.D., Zheng, W., Korach, K.S., Scheuer, T., Catterall, W.A., and Rubanyi, G.M., (1997). Increased expression of the cardiac L-type calcium channel in estrogen receptor-deficient mice. J. Gen. Physiol. 110:135–140.

    PubMed  CAS  Google Scholar 

  238. Chen, Y.F., Naftilan, A.J., and Oparil, S. (1992). Androgen-dependent angiotensinogen and renin messenger RNA expression in hypertensive rats. Hypertension 19: 456–463.

    PubMed  CAS  Google Scholar 

  239. Pelzer, T., Neumann, M., deJager, T., Jazbutyte, V., and Neyses, L. (2001). Estrogen effects in the myocardium: inhibition on NF-κB DNA binding by estrogen receptor-α and-β. Biochem. Biophys. Res. Commun. 286:1153–1157.

    PubMed  CAS  Google Scholar 

  240. Pelzer, T., Schumann, M., Neumann, M. et al. (2000). 17 beta-estradiol prevents programmed cell death in cardiac myocytes. Biochem. Biophys. Res. Commun. 268:192–200.

    PubMed  CAS  Google Scholar 

  241. van Eickels, M., Grohe, C., Cleutjens, J.P., Janssen, B.J., Wellens, H.J., Doevendans, P.A. (2001). 17beta-estradiol attenuates the development of pressure-overload hypertrophy. Circulation 104:1419–1423.

    PubMed  Google Scholar 

  242. Zhai, P., Eurell, T.E., Cooke, P.S., Lubahn, D.B., and Gross, D.R. (2000). Myocardial ischemia-reperfusion injury in estrogen receptor-alpha knockout and wild-type mice. Am. J. Physiol. Heart Circ. Physiol. 278:H1640-H1647.

    PubMed  CAS  Google Scholar 

  243. Camper-Kirby, D., Welch, S., Walker, A. et al. (2001). Myocardial Akt activation and gender: Increased nuclear activity in females versus males. Circ. Res. 88:1020–1027.

    PubMed  CAS  Google Scholar 

  244. Fujio, Y., Nguyen, T., Wencker, D., Kitsis, R.N., and Walsh, K. (2000). Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury inmouse heart. Circulation 101:660–667.

    PubMed  CAS  Google Scholar 

  245. Matsui, T., Li, L., del Monte, F., et al. (1999). Adenoviral gene tranfer of activated phosphatidylinositol 3′-kinase and Akt inhibitits apoptosis of hypoxic cardiomyocytes in vitro. Circulation 100:2373–2379.

    PubMed  CAS  Google Scholar 

  246. Matsui, T., Tao, J., del Monte, F. et al. (2001). Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation 104:330–335.

    PubMed  CAS  Google Scholar 

  247. Dash, R., Schmidt, A.G., Pathak, A. et al. (2003). Differential regulation of p38 mitogen-activated protein kinase mediates gender-dependent catecholamine-induced hypertrophy. Cardiovasc. Res. 57:704–714.

    PubMed  CAS  Google Scholar 

  248. Sasaki, H., Ray, P. S., Zhu, L., Otani, H., Asahara, T., and Maulik, N. (2001). Hypoxia/reoxygenation promotes myocardial angiogenesis via an NF kappa B-dependent mechanism in a rat model of chronic myocardial infarction. J. Mol. Cell. Cardiol. 33:283–294.

    PubMed  CAS  Google Scholar 

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  1. Department of Pharmacology and Cell Biophysics, University of Cincinnati, 231 Albert Sabin Way ML0575, 45267-0575, Cincinnati, OH

    W. Keith Jones, Maria Brown, Xiaoping Ren, Suiwen He & Michael McGuinness

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Jones, W.K., Brown, M., Ren, X. et al. NF-κB as an integrator of diverse signaling pathways. Cardiovasc Toxicol 3, 229–253 (2003). https://doi.org/10.1385/CT:3:3:229

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