Role of nuclear factor κB in cardiovascular health and disease

Heiden, Kim Van der; Simon, Chantal; Luong, Le Anh; Zakkar, Mustafa; Evans, Paul C.

doi:10.1042/cs20090557

Cited by 211 publications

(147 citation statements)

References 152 publications

(161 reference statements)

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“…Since NF-B is one of the major transcription factors that has been linked to both cardiovascular health and diseases, it is not suprising that NF-B has been shown to influence numerous cardiovascular diseases including atherosclerosis (283). The function of NF-B is largely dictated by the genes that it targets for transcription and varies according to stimulus and cell type (283). We are certainly aware that several adipokines induce cardiovascular diseases independent of NF-B; however, this is not part of this review.…”

Section: Adipokines With a Tight Link To Cardiovascular Diseasementioning

confidence: 99%

Inflammation and metabolic dysfunction: links to cardiovascular diseases

Taube

Schlich

Sell

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

203

133

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Abdominal obesity is a major risk factor for cardiovascular disease, and recent studies highlight a key role of adipose tissue dysfunction, inflammation, and aberrant adipokine release in this process. An increased demand for lipid storage results in both hyperplasia and hypertrophy, finally leading to chronic inflammation, hypoxia, and a phenotypic change of the cellular components of adipose tissue, collectively leading to a substantially altered secretory output of adipose tissue. In this review we have assessed the adipo-vascular axis, and an overview of adipokines associated with cardiovascular disease is provided. This resulted in a first list of more than 30 adipokines. A deeper analysis only considered adipokines that have been reported to impact on inflammation and NF-κB activation in the vasculature. Out of these, the most prominent link to cardiovascular disease was found for leptin, TNF-α, adipocyte fatty acid-binding protein, interleukins, and several novel adipokines such as lipocalin-2 and pigment epithelium-derived factor. Future work will need to address the potential role of these molecules as biomarkers and/or drug targets.

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Section: Adipokines With a Tight Link To Cardiovascular Diseasementioning

confidence: 99%

Inflammation and metabolic dysfunction: links to cardiovascular diseases

Taube

Schlich

Sell

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

203

133

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“…Both SOD and H 2 O 2 are known activators of HIF and NF-kB (7,23). Thus, to determine the extent that Hb-induced ROS formation contributed to either HIF or NF-kB activation in our model system, HMECs-1 were cotreated with free Hb species and exogenous SOD and catalase.…”

Section: Antioxidant Treatmentsmentioning

confidence: 99%

Hemoglobin-Induced Endothelial Cell Permeability Is Controlled, in Part, via a Myeloid Differentiation Primary Response Gene–88–Dependent Signaling Mechanism

Lisk¹,

Kominsky²,

Ehrentraut³

et al. 2013

Am J Respir Cell Mol Biol

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The release of hemoglobin (Hb) with hemolysis causes vascular dysfunction. New evidence implicates Hb-induced NF-kB and hypoxia inducible factor (HIF) activation, which may be under the control of a Toll-like receptor (TLR)-signaling pathway. Nearly all TLR-signaling pathways activate the myeloid differentiation primary response gene-88 (MyD88) that regulates NF-kB. We hypothesized that the differing transition states of Hb influence endothelial cell permeability via NF-kB activation and HIF regulation through a MyD88-dependent pathway. In cultured human dermal microvascular endothelial cells (HMECs-1), we examined the effects of Hb in the ferrous (HbFe 21 ), ferric (HbFe 31 ), and ferryl (HbFe 41 ) transition states on NF-kB and HIF activity, HIF-1a and HIF-2a mRNA upregulation, and monolayer permeability, in the presence or absence of TLR4, MyD88, NF-kB, or HIF inhibition, as well as superoxide dismutase (SOD) and catalase. Our data showed that cell-free Hb, in each transition state, induced NF-kB and HIF activity, up-regulated HIF-1a and HIF-2a mRNA, and increased HMEC-1 permeability. The blockade of either MyD88 or NF-kB, but not TLR4, attenuated Hb-induced HIF activity, the up-regulation HIF-1 and HIF-2a mRNA, and HMEC-1 permeability. The inhibition of HIF activity exerted less of an effect on Hb-induced monolayer permeability. Moreover, SOD and catalase attenuated NF-kB, HIF activity, and monolayer permeability. Our results demonstrate that Hb-induced NF-kB and HIF are regulated by two mechanisms, either MyD88 activation or Hb transition state-induced ROS formation, that influence HMEC-1 permeability.Keywords: hemolytic disease; NF-kB; Toll-like receptors; MyD88; sicklecell disease Humans with chronic vascular inflammation and vasoconstriction develop progressive endothelial dysfunction and vascular diseases (e.g., pulmonary arterial hypertension, atherosclerosis, and sickle-cell disease) (1, 2). Vascular diseases develop in the face of chronic hemolysis, as occurs with hemoglobinopathies (including sickle-cell disease), or with the intermittent release of low to moderate levels of plasma-free hemoglobin (Hb), as may be seen in atherosclerosis with intraplaque hemorrhage.Low to moderate levels of plasma-free Hb may, in part, mediate these diseases (1-4). However, studies to date have not fully addressed the complete mechanisms responsible for Hb-induced vascular dysfunction.The a 2 b 2 tetramers of Hb transition safely and effectively between the relaxed (oxy) and tense (deoxy) conformational states, and the oxidation of Hb is controlled by red blood cell catalase, superoxide dismutase (SOD), and ferric Hb reductase. However, after their release from the red blood cell, Hb tetramers and dimers can be oxidized from ferrous (HbFe 21 ) to ferric (HbFe 31 ) (3-5). In theory, HbFe 31 in local tissue environments may react with hydrogen peroxide (H 2 O 2 ) to transition between the ferryl (HbFe 41 ) and HbFe 31 states, leading to heme release, globin chain denaturation, and globin chain crosslinking (4, 5). Oxid...

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“…However, for maintaining the adult heart in a healthy state, a baseline NF-κB activity may be required for antioxidant protection (7). The function of IKK/NF-κB during ischemia/reperfusion injury, myocardial infarction, and subsequent remodeling processes is controversial (1,2). As to myocyte growth, IKK/NF-κB activation in vivo is required for certain forms of hypertrophy (8)(9)(10)(11), but not for others (6,7).…”

mentioning

confidence: 99%

Cardiomyocyte-specific IκB kinase (IKK)/NF-κB activation induces reversible inflammatory cardiomyopathy and heart failure

Maier

Schips²,

Wietelmann³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

162

117

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Inflammation is a major factor in heart disease. IκB kinase (IKK) and its downstream target NF-κB are regulators of inflammation and are activated in cardiac disorders, but their precise contributions and targets are unclear. We analyzed IKK/NF-κB function in the heart by a gain-of-function approach, generating an inducible transgenic mouse model with cardiomyocyte-specific expression of constitutively active IKK2. In adult animals, IKK2 activation led to inflammatory dilated cardiomyopathy and heart failure. Transgenic hearts showed infiltration with CD11b + cells, fibrosis, fetal reprogramming, and atrophy of myocytes with strong constitutively active IKK2 expression. Upon transgene inactivation, the disease was reversible even at an advanced stage. IKK-induced cardiomyopathy was dependent on NF-κB activation, as in vivo expression of IκBα superrepressor, an inhibitor of NF-κB, prevented the development of disease. Gene expression and proteomic analyses revealed enhanced expression of inflammatory cytokines, and an IFN type I signature with activation of the IFN-stimulated gene 15 (ISG15) pathway. In that respect, IKK-induced cardiomyopathy resembled Coxsackievirus-induced myocarditis, during which the NF-κB and ISG15 pathways were also activated. Vice versa, in cardiomyocytes lacking the regulatory subunit of IKK (IKKγ/NEMO), the induction of ISG15 was attenuated. We conclude that IKK/NF-κB activation in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure by inducing an excessive inflammatory response and myocyte atrophy.transcription factors | transgenic mice

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Role of nuclear factor κB in cardiovascular health and disease

Cited by 211 publications

References 152 publications

Inflammation and metabolic dysfunction: links to cardiovascular diseases

Inflammation and metabolic dysfunction: links to cardiovascular diseases

Hemoglobin-Induced Endothelial Cell Permeability Is Controlled, in Part, via a Myeloid Differentiation Primary Response Gene–88–Dependent Signaling Mechanism

Cardiomyocyte-specific IκB kinase (IKK)/NF-κB activation induces reversible inflammatory cardiomyopathy and heart failure

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