Cardiovascular Toxicology

, Volume 3, Issue 3, pp 229–253 | Cite as

NF-κB as an integrator of diverse signaling pathways

The heart of myocardial signaling?
  • W. Keith Jones
  • Maria Brown
  • Xiaoping Ren
  • Suiwen He
  • Michael McGuinness
Article

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.

Keywords

Infarct Size Cardiac Hypertrophy Ischemic Precondition Cardiovascular Toxicology Humana Press Volume IkappaB Kinase 

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Copyright information

© Humana Press Inc. 2003

Authors and Affiliations

  • W. Keith Jones
    • 1
  • Maria Brown
    • 1
  • Xiaoping Ren
    • 1
  • Suiwen He
    • 1
  • Michael McGuinness
    • 1
  1. 1.Department of Pharmacology and Cell BiophysicsUniversity of CincinnatiCincinnati

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