Sustained activation of nuclear factor kappa B and activator protein 1 in chronic heart failure
TL;DR: In experimental and human heart failure, both NF-kappaB and AP-1 are chronically activated in cardiac myocytes, suggesting an important involvement ofNF-kappB andAP-1 in the cardiac remodeling process.
Abstract: Objective: Innate immune response proteins such as inflammatory cytokines, inducible nitric oxide synthase, and toll like receptors are implicated in myocardial depression and left ventricular (LV) remodeling after myocardial infarction (MI). Although all these innate immunity proteins share the downstream activation of the transcription factor NF-κB (nuclear factor kappa B) and activator protein 1 (AP-1), the involvement of NF-κB and AP-1 in LV remodeling has not been demonstrated so far. Methods and results: Nuclear translocation of NF-κB and AP-1 was studied by electrophoretic mobility shift assays and ELISA 10 weeks after large experimental MI in rats, the chronic phase of LV remodeling. In the non-infarcted myocardium of MI rats, NF-κB and AP-1 were significantly activated (2.5-fold) as compared to sham-operated animals. Immunohistochemistry demonstrated NF-κB activation mainly in cardiac myocytes. Treatment with the ACE (angiotensin converting enzyme) inhibitor trandolapril led to a further 2-fold increase in the activation of NF-κB and AP-1 when compared to placebo-treated animals with the same MI size ( P <0.001). Human failing hearts explanted at the time of heart transplantation exhibited marked nuclear translocation of NF-κB in cardiac myocytes when compared to control hearts. NF-κB as well as AP-1 were both significantly activated in congestive heart failure due to ischemic or dilated cardiomyopathy. Conclusion: In experimental and human heart failure, both NF-κB and AP-1 are chronically activated in cardiac myocytes. These findings suggest an important involvement of NF-κB and AP-1 in the cardiac remodeling process.
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TL;DR: A review of the current knowledge of the physiological and pathophysiological functions of NF-kappaB and its possible role as a target of therapeutic intervention is presented in this article.
Abstract: Nuclear factor-kappaB (NF-kappaB) is a major transcription factor that plays an essential role in several aspects of human health including the development of innate and adaptive immunity. The dysregulation of NF-kappaB is associated with many disease states such as AIDS, atherosclerosis, asthma, arthritis, cancer, diabetes, inflammatory bowel disease, muscular dystrophy, stroke, and viral infections. Recent evidence also suggests that the dysfunction of NF-kappaB is a major mediator of some human genetic disorders. Appropriate regulation and control of NF-kappaB activity, which can be achieved by gene modification or pharmacological strategies, would provide a potential approach for the management of NF-kappaB related human diseases. This review summarizes the current knowledge of the physiological and pathophysiological functions of NF-kappaB and its possible role as a target of therapeutic intervention
882 citations
TL;DR: It is shown that the small noncoding RNA microRNA-24 (miR-24) is enriched in cardiac endothelial cells and considerably upregulated after cardiac ischemia, and is suitable for therapeutic intervention in the setting of ischemic heart disease.
Abstract: Background—Myocardial infarction leads to cardiac remodeling and development of heart failure. Insufficient myocardial capillary density after myocardial infarction has been identified as a critical event in this process, although the underlying mechanisms of cardiac angiogenesis are mechanistically not well understood. Methods and Results—Here, we show that the small noncoding RNA microRNA-24 (miR-24) is enriched in cardiac endothelial cells and considerably upregulated after cardiac ischemia. MiR-24 induces endothelial cell apoptosis, abolishes endothelial capillary network formation on Matrigel, and inhibits cell sprouting from endothelial spheroids. These effects are mediated through targeting of the endothelium-enriched transcription factor GATA2 and the p21-activated kinase PAK4, which were identified by bioinformatic predictions and validated by luciferase gene reporter assays. Respective downstream signaling cascades involving phosphorylated BAD (Bcl-XL/Bcl-2–associated death promoter) and Sirtuin...
383 citations
TL;DR: The various molecular signal transduction pathways and the regulators of hypertrophic response including calcineurin, cGMP, NFAT, natriuretic peptides, histone deacetylase, IL-6 cytokine family, Gq/G11 signaling, PI3K, MAPK pathways, Na/H exchanger, RAS, polypeptide growth factors, ANP, NO, TNF-alpha, PPAR and JAK/STAT pathway are discussed
296 citations
Cites background from "Sustained activation of nuclear fac..."
...TNF- and NF- have been shown to be activated in failing hearts of various etiologies, implicating a role of this transcription factor in the pathophysiology of human heart failure [94]....
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TL;DR: The inflammatory phase as a trigger of tissue formation is reviewed in human and experimental myocardial infarction to improve healing of the cardiac wound to maintain structure and function of the heart.
Abstract: In human and experimental myocardial infarction (MI), cessation of blood supply leads to rapid necrosis of cardiac myocytes in the ischaemic heart. Immediately after injury, various intra- and intercellular pathways contribute to healing the myocardial wound in order to achieve tissue integrity and function. MI and the consequent loss of myocardium are the major aetiology for heart failure. Despite aggressive primary therapy, prognosis remains poor in patients with large infarction and severe left ventricular dysfunction. Thus, it would be highly desirable to improve healing of the cardiac wound to maintain structure and function of the heart. Healing in the heart occurs in overlapping phases. Herein, we review the inflammatory phase as a trigger of tissue formation.
276 citations
Cites methods from "Sustained activation of nuclear fac..."
...After permanent coronary artery ligation, activation of NF-kB peaks after 3 days (Figure 2).(22,23) Mice with targeted deletion of the NF-kB subunit p50 are protected from left ventricular dilatation after MI and have preserved left ventricular function....
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TL;DR: The present review will focus on recent studies on the function of NF-kappaB in the cardiovascular system, which has divergent functions and can protect cardiovascular tissues from injury or contribute to pathogenesis depending on the cellular and physiological context.
Abstract: Cardiovascular pathologies are still the primary cause of death worldwide. The molecular mechanisms behind these pathologies have not been fully elucidated. Unravelling them will bring us closer to therapeutic strategies to prevent or treat cardiovascular disease. One of the major transcription factors that has been linked to both cardiovascular health and disease is NF-κB (nuclear factor κB). The NF-κB family controls multiple processes, including immunity, inflammation, cell survival, differentiation and proliferation, and regulates cellular responses to stress, hypoxia, stretch and ischaemia. It is therefore not surprising that NF-κB has been shown to influence numerous cardiovascular diseases including atherosclerosis, myocardial ischaemia/reperfusion injury, ischaemic preconditioning, vein graft disease, cardiac hypertrophy and heart failure. The function of NF-κB is largely dictated by the genes that it targets for transcription and varies according to stimulus and cell type. Thus NF-κB has divergent functions and can protect cardiovascular tissues from injury or contribute to pathogenesis depending on the cellular and physiological context. The present review will focus on recent studies on the function of NF-κB in the cardiovascular system.
211 citations
References
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TL;DR: Recently, significant advances have been made in elucidating the details of the pathways through which signals are transmitted to the NF-kappa B:I kappa B complex in the cytosol and their implications for the study of NF-Kappa B.
Abstract: ▪ Abstract The transcription factor NF-κB, more than a decade after its discovery, remains an exciting and active area of study. The involvement of NF-κB in the expression of numerous cytokines and adhesion molecules has supported its role as an evolutionarily conserved coordinating element in the organism's response to situations of infection, stress, and injury. Recently, significant advances have been made in elucidating the details of the pathways through which signals are transmitted to the NF-κB:IκB complex in the cytosol. The field now awaits the discovery and characterization of the kinase responsible for the inducible phosphorylation of IκB proteins. Another exciting development has been the demonstration that in certain situations NF-κB acts as an anti-apoptotic protein; therefore, elucidation of the mechanism by which NF-κB protects against cell death is an important goal. Finally, the generation of knockouts of members of the NF-κB/IκB family has allowed the study of the roles of these protein...
5,324 citations
TL;DR: It is argued that NF-κB functions more generally as a central regulator of stress responses and pairing stress responsiveness and anti-apoptotic pathways through the use of a common transcription factor may result in increased cell survival following stress insults.
Abstract: Sixteen years have passed since the description of the nuclear factor-кB (NF-кB) as a regulator of к light-chain gene expression in murine B lymphocytes (Sen & Baltimore, 1986a) During that time, over 4,000 publications have appeared, characterizing the family of Rel/NF-кB transcription factors involved in the control of a large number of normal and pathological cellular processes The physiological functions of NF-кB proteins include immunological and inflammatory responses, developmental processes, cellular growth and modulating effects on apoptosis In addition, these factors are activated in a number of diseases, including cancer, arthritis, acute and chronic inflammatory states, asthma, as well as neurodegenerative and heart diseases
3,728 citations
TL;DR: The manuscript and the Figures and Table are based on a manuscript originally written by Gordon C. Dickinson in 2012 and then edited by David I. Dickinson and revised by David A. Dickinson.
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TL;DR: The specific roles of three MAPKs, namely ERK, JNK and FRK, in modulation of both the level and activity of AP-1, are discussed.
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TL;DR: In this paper, an electrophoretic mobility shift assay with end-labeled DNA fragments was used to characterize proteins that bind to the immunoglobulin (Ig) heavy chain and the kappa light chain enhancers.
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