NF-κB in Cardiovascular Disease: Diverse and Specific Effects of a "General" Transcription Factor?

Abstract

The transcription factor NF-kappaB regulates a wide variety of biological effects in diverse cell types and organs, particularly stress and adaptive responses. Recently, it has become recognized that NF-kappaB and its upstream regulator tumor necrosis factor (TNF)-alpha regulate specific antithetical effects. For instance, in the heart, NF-kappaB has been found to be required for development of late preconditioning against myocardial infarction and yet is critically involved in mediating cell death after ischemia/reperfusion injury. There remains a bias that NF-kappaB is a "general" transcription factor that is activated by a plethora of stimuli, including neurohormonal, pathophysiological, and stress stimuli, and affects regulation of numerous downstream genes. The question has become, how can such a "general" transcription factor be critically involved in mediating specific effects? An emerging hypothesis is that NF-kappaB is part of a complicated signaling network or web, and that different combinatorial interactions between various activated signaling pathway components produce specific outcomes. This idea is supported by the large number of interactions discovered in the past 14 years between NF-kappaB and other signaling pathways at multiple levels. Notwithstanding the complexities of signal-induced activation of NF-kappaB, since it is a transcription factor, specific effects of NF-kappaB activation must be underlain by the activation and/or suppression of distinct subsets of NF-kappaB-dependent genes. At this level, selectivity is conferred by the expression of specific NF-kappaB subunits, their post translational modifications, and by combinatorial interactions between NF-kappaB and other transcription factors and coactivators that form specific enhanceosome complexes in association with particular promoters. These enhanceosome complexes represent another level of signaling integration whereby the activities of multiple upstream pathways converge to impress a distinct pattern of gene expression upon the NF-kappaB-dependent transcriptional network. Understanding how the overall cellular signaling network translates NF-kappaB activation into the regulation of specific subsets of NF-kappaB-dependent genes will lead to a mechanistic understanding of how NF-kappaB mediates diverse and paradoxical biological effects.

Neutralization of Interleukin-18 Ameliorates Ischemia/Reperfusion-induced Myocardial Injury

“…6). NF-B is an inducible, oxidative stress-responsive multisubunit transcription factor involved in the induction of diverse B-responsive genes including cytokines, chemokines, and adhesion molecules (31,34). Both I/R in vivo and sI/R in vitro induced the activation of NF-B, comprising predominantly p50 and p65 subunits.…”

“…Simulated I/R induced IB-␣ degradation in an IKK␤-dependent manner and stimulated the phosphorylation of p65, suggesting that I/R induces NF-B activation via several mechanisms. Activation of NF-B may lead to the inflammation, inflammatory cell recruitment, and cell death characteristic of ischemic heart disease (31,34).…”

Peroxisome Proliferator-Activated Receptor-γ–Mediated Effects in the Vasculature

“…15,16 It is the major target for PPAR-␥ to suppress inflammation. 17,18 NF-B mediates the inflammatory responses in vascular cells, 19 and its activation significantly contributes to the development of vascular disorders such as atherosclerosis 20,21 and hypertension. 22 …”

Involvement of Nuclear Factor κB (NF-κB) Signaling Pathway in Regulation of Cardiac G Protein-coupled Receptor Kinase 5 (GRK5) Expression

“…In HF, NF-B may play a detrimental role by up-regulating the expression of TNF-␣ and other proinflammatory molecules but may also have beneficial roles for the resolution of inflammation and in tissue remodeling because it regulates several antiapoptotic genes (9,12). NF-B is activated by multiple stimuli, including those present in ischemic and hypertrophic myocardium (9,10). TNF-␣ is a potent stimulator of NF-B activity, and it can also be activated in cardiomyocytes by specific GPCR agonists, especially those that induce hypertrophy (9, 13), which could have a direct influence on nuclear GRK5 activity.…”