Year: 2012
Type: article
Abstract: See related article on page 1530 See related article on page 1530 Hypoxia, a decrease in oxygen tension within tissues, occurs in response to several pathophysiological disease states, including myocardial ischemia, atherosclerosis, and obstructive sleep apnea. HIF-1α, a basic helix-loop-helix transcription factor and a master regulator of cellular homeostatic responses to hypoxia, activates transcription of genes involved in energy metabolism, angiogenesis, apoptosis, and cell differentiation. HIF-1α is regulated post-transcriptionally by prolyl hydroxylases under normoxic conditions, an effect that allows for their recognition and ubiquitination by the von Hippel-Lindau E3 ubiquitin ligase and rapid degradation by the proteasome.1Maxwell P.H. Wiesener M.S. Chang G.W. Clifford S.C. Vaux E.C. Cockman M.E. Wykoff C.C. Pugh C.W. Maher E.R. Ratcliffe P.J. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.Nature. 1999; 399: 271-275Crossref PubMed Scopus (4238) Google Scholar, 2Bruick R.K. McKnight S.L. A conserved family of prolyl-4-hydroxylases that modify HIF.Science. 2001; 294: 1337-1340Crossref PubMed Scopus (2160) Google Scholar, 3Jaakkola P. Mole D.R. Tian Y.M. Wilson M.I. Gielbert J. Gaskell S.J. von Kriegsheim A. Hebestreit H.F. Mukherji M. Schofield C.J. Maxwell P.H. Pugh C.W. Ratcliffe P.J. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.Science. 2001; 292: 468-472Crossref PubMed Scopus (4585) Google Scholar However, accumulating data indicate that HIF-1α may also be regulated in response to inflammatory stimuli in an NF-κB–dependent manner.4van Uden P. Kenneth N.S. Rocha S. Regulation of hypoxia-inducible factor-1alpha by NF-kappaB.Biochem J. 2008; 412: 477-484Crossref PubMed Scopus (556) Google Scholar, 5Rius J. Guma M. Schachtrup C. Akassoglou K. Zinkernagel A.S. Nizet V. Johnson R.S. Haddad G.G. Karin M. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha.Nature. 2008; 453: 807-811Crossref PubMed Scopus (1222) Google Scholar The interplay between hypoxia and inflammation, along with its pathological role in acute and chronic inflammatory disease states such as atherosclerosis, has emerged as a subject of significant scientific interest.6Eltzschig H.K. Carmeliet P. Hypoxia and inflammation.N Engl J Med. 2011; 364: 656-665Crossref PubMed Scopus (1506) Google Scholar Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH) as a result of repetitive episodes of complete or partial obstructions of the upper airway during sleep, is an independent risk factor for the development of cardiovascular disease. Furthermore, the prevalence of OSA has been estimated to be as high as 50% in persons with cardiometabolic disorders.7Lurie A. Obstructive sleep apnea in adults: epidemiology, clinical presentation, and treatment options.Adv Cardiol. 2011; 46: 1-42Crossref PubMed Scopus (155) Google Scholar Atherosclerosis, a chronic inflammatory disease of the arterial wall, develops in a more aggressive manner in the context of OSA.8Drager L.F. Polotsky V.Y. Lorenzi-Filho G. Obstructive sleep apnea: an emerging risk factor for atherosclerosis.Chest. 2011; 140: 534-542Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, 9Arnaud C. Dematteis M. Pepin J.L. Baguet J.P. Levy P. Obstructive sleep apnea, immuno-inflammation, and atherosclerosis.Semin Immunopathol. 2009; 31: 113-125Crossref PubMed Scopus (94) Google Scholar Experimentally, CIH initiates atherosclerosis in the presence of high-fat, diet-induced dyslipidemia in both wild-type C57BL/6J mice10Savransky V. Nanayakkara A. Li J. Bevans S. Smith P.L. Rodriguez A. Polotsky V.Y. Chronic intermittent hypoxia induces atherosclerosis.Am J Respir Crit Care Med. 2007; 175: 1290-1297Crossref PubMed Scopus (331) Google Scholar and atherosclerotic-prone ApoE knockout (ApoE-KO) mice,11Jun J. Reinke C. Bedja D. Berkowitz D. Bevans-Fonti S. Li J. Barouch L.A. Gabrielson K. Polotsky V.Y. Effect of intermittent hypoxia on atherosclerosis in apolipoprotein E-deficient mice.Atherosclerosis. 2010; 209: 381-386Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar effects that established a causal link between CIH and atherosclerosis. More recent studies suggest that RANTES/CCL5 signaling, leukotriene B4 pathway activation, and several other inflammatory components contribute to CIH-induced atherosclerosis.12Arnaud C. Poulain L. Levy P. Dematteis M. Inflammation contributes to the atherogenic role of intermittent hypoxia in apolipoprotein-E knock out mice.Atherosclerosis. 2011; 219: 425-431Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 13Arnaud C. Beguin P.C. Lantuejoul S. Pepin J.L. Guillermet C. Pelli G. Burger F. Buatois V. Ribuot C. Baguet J.P. Mach F. Levy P. Dematteis M. The inflammatory preatherosclerotic remodeling induced by intermittent hypoxia is attenuated by RANTES/CCL5 inhibition.Am J Respir Crit Care Med. 2011; 184: 724-731Crossref PubMed Scopus (105) Google Scholar, 14Li R.C. Haribabu B. Mathis S.P. Kim J. Gozal D. Leukotriene B4 receptor-1 mediates intermittent hypoxia-induced atherogenesis.Am J Respir Crit Care Med. 2011; 184: 124-131Crossref PubMed Scopus (70) Google Scholar Despite these observations, the mechanisms by which outside-in hypoxic signaling accelerates the initiation and progression of atherosclerosis are poorly understood, in part because of the limitations of current animal models for CIH-induced atherosclerosis; such models typically involve exposure to CIH in animals with pre-existing atherosclerotic pathology, potentially obscuring the initiation phase of lesion development. Furthermore, because activation of NF-κB (particularly in the vascular endothelium) has been linked to increased atherosclerotic lesion formation, it has been hypothesized that the loss of NF-κB family members may reduce atherosclerosis, including atherosclerosis in response to CIH. In this issue, Fang et al15Fang G. Song D. Ye X. Mao S.Z. Liu G. Liu S.F. Chronic intermittent hypoxia exposure induces atherosclerosis in ApoE knockout mice: role of NF-kappaB p50.Am J Pathol. 2012; 181: 1530-1539Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar report development of two new mouse models of CIH-induced atherosclerosis; their study, surprisingly, revealed that loss of the NF-κB p50 subunit increased atherosclerosis in the presence of CIH. In the first model, ApoE-KO mice were fed a normal chow diet and exposed to CIH. After 9 weeks of CIH exposure, no obvious lesions were observed in the thoracic and abdominal aorta, compared with sham-exposed ApoE-KO mice; a trend toward increased numbers of lesions in the aortic root did not reach significance. After 30 weeks of CIH exposure, however, atherosclerotic lesion areas increased in both the aortic root and the thoracic-abdominal aorta. Importantly, lesion areas of ApoE-KO mice given a high-fat diet were approximately threefold greater than in CIH-exposed ApoE-KO mice, suggesting that CIH is a much weaker physiological stimulus for atherosclerotic lesion formation, compared with dyslipidemia. In the second model, compound ApoE and p50 double-knock-out mice (ApoE-p50-DKO) were fed a normal chow diet and exposed to CIH. Remarkably, after 9 weeks of CIH exposure, atherosclerotic lesion formation increased approximately 2.5-fold in ApoE-p50-DKO mice, compared with CIH-exposed ApoE-KO mice. Thus, ApoE-KO mice with systemic deficiency of p50 are more sensitive to CIH-induced atherogenesis, suggesting an atheroprotective role of the NF-κB p50 subunit in the presence of CIH. Examination of the NF-κB signaling pathway revealed a reduction in IκBα expression in CIH-ApoE-KO mice, indicating activation of the canonical NF-κB pathway. Interestingly, supershift assays of NF-κB DNA-protein binding showed that the CIH-induced NF-κB complex in ApoE-KO mice is composed predominantly of p50/p50 homodimers, with minor contributions from c-Rel/p50 and likely also p65/p50 heterodimers. NF-κB DNA-binding was severely decreased by p50 gene deletion in ApoE-KO mice, particularly in response to CIH (Figure 1). Importantly, the expression of the proinflammatory NF-κB target genes TNF, IL6, and NOS2 (encoding TNF-α, IL-6, and iNOS, respectively) was increased by CIH, and NF-κB p50 deletion further increased their expression, an effect that was associated with aortic accumulation of Mac3-positive macrophages. Nonetheless, some caution is indicated in interpreting the accelerated atherosclerotic phenotype in ApoE-p50-DKO mice, given that these mice exhibited increased serum total cholesterol levels. Such increased serum total cholesterol levels can potentially contribute to lesion formation through excessive intralesional macrophage foam-cell formation, among other mechanisms. Although the mechanism by which p50 deficiency increases total cholesterol remains unclear (despite absence of changes in LDL, HDL, or triglyceride fractions), mRNA expression of hepatic LDL receptor, which participates in LDL-mediated cholesterol uptake and clearance, was significantly reduced. Further studies will be required to determine how p50 regulates LDL receptor expression and/or LDL formation and the relative contribution of a 1.7-fold increase in cholesterol in the CIH-exposed ApoE-p50-DKO mice. Nevertheless, the study by Fang et al15Fang G. Song D. Ye X. Mao S.Z. Liu G. Liu S.F. Chronic intermittent hypoxia exposure induces atherosclerosis in ApoE knockout mice: role of NF-kappaB p50.Am J Pathol. 2012; 181: 1530-1539Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar provides a mechanistic understanding of how outside-in hypoxia signaling promotes atherosclerosis, without the limitations of prior models confounded by pre-existing atherosclerosis. Although their study revealed a protective role of NF-κB p50 in CIH-induced atherosclerosis, the initiating events linking hypoxia to NF-κB–mediated inflammation remain incompletely understood. Emerging studies have revealed several mechanistic paradigms that link NF-κB and hypoxia signaling pathways. The NF-κB transcription factor family consists of five members: RelA, RelB, c-Rel, p50, and p52. RelA, RelB, and c-Rel contain a C-terminal transactivation domain, but no definable activation domains are found in p50 and p52. NF-κB p50 is processed from its precursor p105. The precursor p105 functions as an NF-κB inhibitor, blocking the activity of its dimeric NF-κB partners and retaining them in the cytoplasm. The NF-κB family members can form different homo- and heterodimers, with each dimer being involved in the regulation of a unique set of target genes. The p65/p50 heterodimer, which represents the most abundant NF-κB dimer, is activated in response to proinflammatory stimuli (such as TNF-α, IL-1β, and LPS) in almost all cell types through the canonical NF-κB signaling pathway. RelB/p52 heterodimers are activated by lymphotoxin, B-cell activating factor, or CD40 ligand via the noncanonical NF-κB pathway, which involves inducible proteolytic removal of the ankyrin-repeat domain of p100/RelB heterodimers. Several other heterodimers containing p50 have been described, including p50/c-Rel, p50/p50, and p50/RelB. For example, p50/c-Rel heterodimers are the primary component of constitutively active NF-κB observed in mature B cells. However, not all NF-κB dimers are transcriptionally active; in particular, p50/p50 homodimers have been found to transcriptionally repress target genes by preventing transactivation domain-containing NF-κB dimers from binding to κB sites in unstimulated or resting cells.16Grundström S. Anderson P. Scheipers P. Sundstedt A. Bcl-3 and NFkappaB p50-p50 homodimers act as transcriptional repressors in tolerant CD4+ T cells.J Biol Chem. 2004; 279: 8460-8468Crossref PubMed Scopus (77) Google Scholar Alternatively, p50 may interact with histone deacetylases or other coregulators that inhibit an activator of target genes.17Elsharkawy A.M. Oakley F. Lin F. Packham G. Mann D.A. Mann J. The NF-kappaB p50: p50:HDAC-1 repressor complex orchestrates transcriptional inhibition of multiple pro-inflammatory genes.J Hepatol. 2010; 53: 519-527Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 18Ashburner B.P. Westerheide S.D. Baldwin Jr, A.S. The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression.Mol Cell Biol. 2001; 21: 7065-7077Crossref PubMed Scopus (637) Google Scholar, 19Kumar A. Lin Z. SenBanerjee S. Jain M.K. Tumor necrosis factor alpha-mediated reduction of KLF2 is due to inhibition of MEF2 by NF-kappaB and histone deacetylases.Mol Cell Biol. 2005; 25: 5893-5903Crossref PubMed Scopus (137) Google Scholar Indeed, p50/p50 homodimers repress the expression of NF-κB target genes, such as those encoding TNF-α, IL-6, and IL-8.20Baer M. Dillner A. Schwartz R.C. Sedon C. S. Johnson Tumor necrosis factor transcription in is attenuated by an factor that induces NF-kappaB Cell Biol. PubMed Google Scholar, X. L. C. The p50-p50 NF-kappaB complex as a repressor of gene Cell 2004; PubMed Scopus Google Scholar, M. M. S. K. The protein in of the 2005; PubMed Scopus (155) Google Scholar For example, during exposure to the binding of p50 homodimers to the κB sites the transcriptional activation and the of J. S. Regulation of an innate response by the p50 subunit of PubMed Scopus Google Scholar with these Fang et al15Fang G. Song D. Ye X. Mao S.Z. Liu G. Liu S.F. Chronic intermittent hypoxia exposure induces atherosclerosis in ApoE knockout mice: role of NF-kappaB p50.Am J Pathol. 2012; 181: 1530-1539Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar found that TNF-α, IL-6, and were induced in CIH-exposed ApoE-KO mice and that the was further in the absence of p50, suggesting that p50 a for the gene expression of these in response to CIH. data also that the relative of NF-κB is for gene expression (Figure 1). Interestingly, found that the CIH-induced NF-κB complex is composed of p50/p50 homodimers, of c-Rel/p50 and likely also p65/p50 heterodimers loss of transcriptionally p50 may for increased and transcriptional activity of c-Rel/p50 or p65/p50 heterodimers on to TNF-α, IL-6, and expression in response to CIH. data from several studies indicate significant between the and NF-κB signaling pathways. In response to hypoxia, the canonical NF-κB pathway is in by inhibition of prolyl hydroxylases that negatively regulate activation by hypoxia to IκBα and by NF-κB p65 binding to κB and of gene J. Guma M. Schachtrup C. Akassoglou K. Zinkernagel A.S. Nizet V. Johnson R.S. Haddad G.G. Karin M. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha.Nature. 2008; 453: 807-811Crossref PubMed Scopus (1222) Google Scholar, A. F. C. P. 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NF-kappaB inhibition mice from 2008; Full Text Full Text PDF PubMed Scopus Google Scholar on several mouse models with NF-κB studies revealed that NF-κB to a reduction in atherosclerotic lesion inducible atherosclerosis by in and in and IκBα expression atherosclerotic by Although it is that NF-κB activation promotes the initiation and progression of atherosclerosis, the role of NF-κB signaling in atherosclerosis remains NF-κB an role in cell et M. K. G. of NF-kappaB activation in increases atherosclerosis in LDL PubMed Scopus Google Scholar showed that deletion increased atherosclerosis in mice. NF-κB in may lesion development in mouse models of atherosclerosis. deletion of p50 in to atherosclerotic lesion formation in P. G. deficiency in atherosclerotic lesions with an inflammatory 2004; PubMed Scopus (94) Google Scholar lesions exhibited a more inflammatory with numbers of T and B cells. lesions in these mice exhibited a complete absence of likely because of of and decreased expression of receptor A. Interestingly, of of IκBα in decreased by macrophage and decreased foam-cell Fang et al15Fang G. Song D. Ye X. Mao S.Z. Liu G. Liu S.F. Chronic intermittent hypoxia exposure induces atherosclerosis in ApoE knockout mice: role of NF-kappaB p50.Am J Pathol. 2012; 181: 1530-1539Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar in ApoE-p50-DKO mice, CIH did not cholesterol was no in hepatic and or the expression of is the master regulator of cholesterol and did not increase cholesterol LDL receptor expression was however, and the reduction of hepatic expression may be an component of the observed that further these clinical because persons with OSA have a prevalence of dyslipidemia than those without L.F. J. Polotsky V.Y. Obstructive sleep apnea and for atherosclerosis in 2010; PubMed Scopus Google Scholar NF-κB has been in pathological states, including cardiovascular and other may be to to these by NF-κB activation without the particularly from several blocking NF-κB activation in animal models have involved that reduce the activity of or their that of to that target NF-κB by the that inhibit NF-κB DNA-protein binding to and that reduce NF-κB X. B. S. L. regulates vascular 2012; Google Scholar, C. M. regulation of proinflammatory phenotype in in and in 2010; PubMed Scopus Google Scholar Several have been in clinical including a that the activation of by and also an receptor which in was by the and for the treatment of with receptor also and in Several that are to inhibit NF-κB are in clinical as The and of several NF-κB are being in a of clinical In the cardiovascular several have effects on NF-κB activity or NF-κB target gene these and Although of NF-κB are for in cardiovascular the study by Fang et al15Fang G. Song D. Ye X. Mao S.Z. Liu G. Liu S.F. Chronic intermittent hypoxia exposure induces atherosclerosis in ApoE knockout mice: role of NF-kappaB p50.Am J Pathol. 2012; 181: 1530-1539Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar provides including the that inhibition of NF-κB that p50/p50 homodimers may have effects in the context of CIH and G. Song D. Ye X. Mao S.Z. Liu G. Liu S.F. Chronic intermittent hypoxia exposure induces atherosclerosis in ApoE knockout mice: role of NF-kappaB p50.Am J Pathol. 2012; 181: 1530-1539Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar the prevalence of and atherosclerosis in OSA the expression or of NF-κB p50 may new targets in these for cardiovascular disease. the of coregulators to the p50/p50 NF-κB complex may have a particularly for the of CIH-induced atherosclerosis. these events may the of targets in persons with obstructive sleep apnea, atherosclerosis, or chronic disease Chronic Hypoxia in ApoE of NF-κB of animal models of chronic intermittent hypoxia atherosclerosis have of CIH-induced atherosclerosis are poorly understood. study new mouse models of CIH-induced atherosclerosis and the role of NF-κB p50 in CIH-induced atherosclerosis. in apolipoprotein (ApoE-KO) or in both ApoE and p50 genes (ApoE-p50-DKO) were exposed to or CIH. lesions on aortic were CIH exposure atherosclerosis in ApoE-KO mice fed a normal chow diet and with no atherosclerotic in an exposure PDF
Source: American Journal Of Pathology
Authors: Xinghui Sun, Mark W. Feinberg
Institutions: Brigham and Women's Hospital, Harvard University
Language: English
Topic: NF-κB Signaling Pathways
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $2,800
OpenAlex ID: W205116534