HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Valen, G. Articles by Hansson, G.o. K. Search for Related Content PubMed PubMed Citation Articles by Valen, G. Articles by Hansson, G.o. K.

REVIEW ARTICLE

Nuclear factor kappa-B and the heart

Guro Valen, MD, PhD^*, Zhong-qun Yan, PhD and G.öran K. Hansson, MD, PhD

^* Crafoord Laboratory of Experimental Surgery, Karolinska Hospital, Stockholm, Sweden
Center of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden

Manuscript received November 29, 2000; revised manuscript received April 11, 2001, accepted April 25, 2001.

Reprint requests and correspondence: Dr. Guro Valen, Crafoord Laboratory of Experimental Surgery L6:00, Karolinska Hospital, S-171 76 Stockholm, Sweden
Guro.Valen{at}cmm.ki.se

	Abstract

Top Abstract Activation of NF{kappa}B Cell biological effects of... NF{kappa}B in apoptosis NF{kappa}B in myocardial... NF{kappa}B in ischemic... A role for NF{kappa}B... NF{kappa}B in heart failure Summary References

 
Nuclear factor kappa-B (NFB), a redox-sensitive transcription factor regulating a battery of inflammatory genes, has been indicated to play a role in the development of numerous pathological states. Activation of NFB induces gene programs leading to transcription of factors that promote inflammation, such as leukocyte adhesion molecules, cytokines, and chemokines, although some few substances with possible anti-inflammatory effects are also NFB regulated. The present article reviews basic regulation of NFB and its activation, cell biological effects of NFB activation and the role of NFB in apoptosis. Evidence involving NFB as a key factor in the pathophysiology of ischemia-reperfusion injury and heart failure is discussed. Although activation of NFB induces pro-inflammatory genes, it has lately been indicated that the transcription factor is involved in the signaling of endogenous myocardial protection evoked by ischemic preconditioning. A possible role of NFB in the development of atherosclerosis and unstable coronary syndromes is discussed. Nuclear factor kappa-B may be a new therapeutic target for myocardial protection.

Abbreviations and Acronyms   IAP = inhibitor of apoptosis   ICAM = intercellular adhesion molecule   IL = interleukin   IB = inhibitory kappa-B   IKK = inhibitory kappa-B kinase complex   LPS = lipopolysaccharide   MAPK = mitogen-activated protein kinase   NFB = nuclear factor kappa-B   NO = nitric oxide   TLR = toll-like receptor   TNF- = tumor necrosis factor-alpha   XIAP = X-linked inhibitor of apoptosis protein

	Activation of NFB

Top Abstract Activation of NF{kappa}B Cell biological effects of... NF{kappa}B in apoptosis NF{kappa}B in myocardial... NF{kappa}B in ischemic... A role for NF{kappa}B... NF{kappa}B in heart failure Summary References

 
Nuclear factor kappa-B can be activated by reactive oxygen intermediates, hypoxia/anoxia, hyperoxia, cytokines, protein kinase C activators, mitogen-activated protein kinase (MAPK) activators, bacterial or viral products, such as lipopolysaccharide (LPS), dsRNA, or the human T-cell leukemia virus type 1 Tax protein, and by UV-radiation (1–7). A schematic presentation of NFB activation is shown in Figure 1. NFB regulates genes involved in both innate and adaptive immunity, among them pro-inflammatory cytokines, chemokines, leukocyte adhesion molecules and inflammatory enzymes (for details see reviews 1–4). The NFB family consists of the members p50, p52, p65 (RelA), c-Rel, and RelB, which form various homo- and heterodimers, where the most common active form is the p50 or p52/RelA heterodimer. The NFB dimers in resting cells reside in the cytoplasm in an inactive form bound to inhibitory proteins known as IB. At least six IB proteins are involved in controlling the activity of the NFB dimer (1–4). Both IB and IBß, the two stimulus-regulatory proteins of NFB, have two N-terminal serine residues that are phosphorylated in response to diverse stimuli. The phosphorylated IBs are then ubiquitinated and proteolytically degraded. This process activates NFB, which translocates to the nucleus and binds to promoter or enhancer regions of specific genes, initiating transcription (1–4).

View larger version (31K): [in this window] [in a new window]   Figure 1 A schematic presentation of activation of the transcription nuclear factor kappa-B (NFB). In the cytoplasm of the resting cell, the NFB dimer, often consisting of the subunits p50/p65, is bound to inhibitory proteins known as inhibitory kappa-B (IB). Stimuli activating IB kinases will cause nuclear translocation of the NFB dimer, while IB is proteolytically degraded. In the nucleus, NFB binds to consensus sites in promoter/enhancer regions of genes it regulates, and transcription of these substances commences. COX-2 = cyclo-oxygenase-2 inhibitor; ICAM-2 = intercellular adhesion molecule 2; IL = interleukin; iNOS = inducible nitric oxide synthase; LPS = lipopolysaccharide; MHC = major histocompatibility complex; TNF = tumor necrosis factor; VCAM-1 = vascular cell adhesion molecule-1.

Recently, an additional IKK complex has been suggested (20). This novel IKK complex contains an IB kinase referred as to IKK. Intriguingly, the purified IKK is capable of phosphorylating only one of the serine residues, S32, but not S36 of IB. However, the endogenous IKK derived from phorbol myristate acetate-treated cells could phosphorylate both S32 and S36, implying the possibility of another unknown IB kinase existing in the IKK complex. In addition, an LPS-inducible IB kinase, IKKi, has also been identified (21). Expression of IKKi can be induced, particularly in immune cells in response to LPS and pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-), interleukin (IL)-1ß and IL-6. Overexpression of IKKi results in phosphorylation of IB, preferentially S36. Moreover, IKKi has been shown to phosphorylate TRAF1 as well as to induce c-Jun N-terminal kinase upon stimulation (22). Thus, IKKi may have more divergent functions than the other IKKs.

The kinase cascades for NFB-activation may follow several stimulus-dependent pathways. For example, protein kinase C, protein kinase A, protein kinase R, Raf, eukaroytic initiation factor-2-kinase, casein kinase II and mitogen-activated kinase can phosphorylate IB without being site-specific (not on serine residues). Site-specific kinases discussed above predominantly phosphorylate IKKß (2–4). The composition of the NFB dimer and its regulatory protein, the nature of the stimulus and the number of concensus sites in the target gene will influence the activity and amount of transcribed product after NFB activation. Additionally, NFB works in cooperation with other transcription factors, in particular, activator protein-1 (AP-1) (1,23).

	Cell biological effects of NFB activation

Top Abstract Activation of NF{kappa}B Cell biological effects of... NF{kappa}B in apoptosis NF{kappa}B in myocardial... NF{kappa}B in ischemic... A role for NF{kappa}B... NF{kappa}B in heart failure Summary References

 
Pro-inflammatory cytokines produced by macrophages, T cells and other cells exert their actions on target cells by transactivating NFB (i.e., by initiating the signal cascade described above) (3,24,25). Most cells express receptors for the pro-inflammatory cytokines, IL-1ß and TNF-, and they also contain the IKK complex needed for signal transduction. Cells such as leukocytes, vascular endothelial and smooth muscle cells, cardiomyocytes and fibroblasts therefore respond to pro-inflammatory cytokines by NFB activation (3,24–26). This leads to or enhances expression of a host of genes, including those encoding several cytokines (e.g., IL-6 and IL-12), leukocyte adhesion molecules (e.g., ICAM-1, VCAM-1, E-selectin), matrix metalloproteinases, cyclooxygenase-2 and inducible nitric oxide (NO) synthase (27–34). Also, NFB activation induces the expression of pro-inflammatory cytokines in a positive feedback loop. By inducing secretion of IL-6, NFB-mediated stimuli act on the liver and brain to cause the systemic signs of inflammation (35).

The NFB pathway is used not only by pro-inflammatory cytokines but also by microbial products. In particular, endotoxins of gram-negative bacteria signal through NFB after ligation of their LPS moieties to receptors of the Toll-like receptor (TLR) family (36,37). This gene family is named after the Toll gene, a developmental regulatory gene in Drosophila. Recently, TLR-4 was identified as the signaling LPS receptor in man and other mammals (36,37). Septic shock therefore causes symptoms indistinguishable from those elicited when immune cells are activated to produce pro-inflammatory cytokines (37). Both TLRs, NFB and downstream products such as NO, are phylogenetically old molecules, and it is likely that TLR/NFB–mediated response to bacteria has been a key mechanism through evolution for the protection of multicellular organisms against pathogenic invaders.

	NFB in apoptosis

Top Abstract Activation of NF{kappa}B Cell biological effects of... NF{kappa}B in apoptosis NF{kappa}B in myocardial... NF{kappa}B in ischemic... A role for NF{kappa}B... NF{kappa}B in heart failure Summary References

 
Because the NFB pathway is involved in pathological responses, it was believed to activate cell-death pathways. In endotoxinemia, acute and overwhelming NFB activation can indeed lead to widespread endothelial cell death with permeability disturbances and disseminated coagulation (26). However, it has become apparent that NFB can also protect cells from death. Tumor necrosis factor-alpha can cause programmed cell death (i.e., apoptosis), and this is often paralleled by increased NFB activation (38). Surprisingly, inhibition of NFB increased rather than reduced cell death in these experiments (39). This would suggest that NFB can actually serve as a survival factor. Such a protective role for NFB was also observed in p65/RelA knockout mice, which died embryonally from extensive liver apoptosis (40). A similar conclusion was reached in studies of vascular smooth muscle cells, in which TNF- can also induce programmed cell death (41). These cells express NFB constitutively (42). If NFB is inhibited (e.g., by the chemical pyrrolidine dithiocarbamate or by transfecting a virus that overexpresses IB), the smooth muscle cells die (43,44).

The paradoxical "survival" action of NFB is due to an induction of antiapoptotic factors (40,45). In particular, the genes for inhibitor of apoptosis protein-1 (IAP-1) (46) and X-linked inhibitor of apoptosis protein (XIAP) contain NFB elements in its promoters (43,47). The NFB transactivation leads to IAP-1 and XIAP gene expression, and the protein product inhibits several of the caspase enzymes involved in the cell-death program. Additionally, NFB may upregulate the mitochondrial antiapoptotic factor Bcl-2 (48), perhaps in a positive feedback loop as Bcl-2 downregulates IB, thus increasing NFB activation (49). Additional feedback loops modulate NFB activation during cytokine signaling and the apoptotic cascade. For instance, caspase 8 can inactivate the kinase RIP that is needed for TNF-induced NFB activation (50). Activation of the caspase cascade during apoptosis therefore downregulates NFB-dependent antiapoptotic pathways.

Studies in different experimental models support the notion that NFB can protect cells from death. For instance, loss of one of the NFB subunits reduces cell death in an ischemia/reperfusion stroke model (51). The IKK –/– mice die at midgestation owing to massive liver apoptosis, and IKK-deficient cells are sensitive to TNF-induced apoptosis (52–54). Why can NFB induce both survival signals and detrimental molecules? A likely explanation may be that the inflammatory program mediated through NFB activation generates toxic molecules that can kill invading microorganisms without damaging the host cells. The induction by NFB of a survival program in parallel with potentially dangerous enzymes such as matrix metalloproteinase-9 and NO synthase (28,55,56) might therefore provide protection for the cytokine-responding cell. In addition, NFB-mediated expression of iNOS will eventually lead to an NO-dependent increase in IB expression (57); this is likely to turn off the cytokine program that involves signals for death as well as survival and activation (58). It is apparent that the role of NFB in the regulation of cell viability is multidimensional and much further work will be needed for a complete understanding of these mechanisms.

	NFB in myocardial ischemia-reperfusion

Top Abstract Activation of NF{kappa}B Cell biological effects of... NF{kappa}B in apoptosis NF{kappa}B in myocardial... NF{kappa}B in ischemic... A role for NF{kappa}B... NF{kappa}B in heart failure Summary References

 
Nuclear factor kappa-B is activated by myocardial ischemia and reperfusion (59–61), including in the human heart subjected to cardioplegia and reperfusion during open heart surgery (62). In isolated hearts this starts shortly after initiation of ischemia and is augmented by reperfusion (59). In hearts subjected to in vivo infarction, NFB-activation is biphasic, peaking after 15 min and 3 h reperfusion, possibly corresponding to a primary activation by reactive oxygen intermediates and a secondary activation by pro-inflammatory cytokines produced by the first activation (60). A detrimental role of NFB during reperfusion is suggested indirectly by functional studies of the genes it regulates: inhibition of leukocyte adhesion, cytokines, and chemokines during reperfusion protects the heart against reperfusion injury (61,63–65).

More direct evidence for a detrimental role of NFB is supplied by Morishita et al. (66), who transfected rats intracoronary with a double-stranded oligonucleotide containing the NFB cis-element before coronary artery ligation. The decoy inhibited NFB activation during reperfusion and concomitantly reduced infarct size (66). When the decoy was used for transfection and heterotopic transplantation three days prior to Langendorff-perfusion with Krebs-Henseleit buffer containing rat leukocytes, improved cardiac function during reperfusion was found together with reduced neutrophil adherence and tissue IL-8 production (67). Several of the genes that NFB regulates, such as cytokines and leukocyte adhesion molecules, are implemented in reperfusion injury (61,63–65). Finally, a role of NFB-activation in cardiac allograft rejection has been suggested, as pharmacological inhibition of NFB prolongs survival of heterotopic transplants (68).

	NFB in ischemic preconditioning

Top Abstract Activation of NF{kappa}B Cell biological effects of... NF{kappa}B in apoptosis NF{kappa}B in myocardial... NF{kappa}B in ischemic... A role for NF{kappa}B... NF{kappa}B in heart failure Summary References

 
Ischemic preconditioning (short episodes of ischemia and reperfusion), which profoundly reduces infarct size and improves cardiac function during reperfusion, can be performed less than 2 h (classic preconditioning) or 24 to 72 h (delayed preconditioning) before sustained ischemia. However, the clinical application is thus far hampered by failure to determine mechanisms underlying the response. A possible role for NFB in ischemic preconditioning has recently been suggested (69–71). Indirect evidence for this is provided by the intracellular signaling pathways of preconditioning in rats and rabbits: activation of protein kinase C, tyrosine kinase and p38 MAPK appears to be crucial for the response, and these kinases also activate NFB (69,70,72). The NFB is activated during the preconditioning episodes, and pharmacological inhibition of NFB abolishes the cardioprotection in both classic and delayed models (69–71). Trigger substances for preconditioning are suggested to be reactive oxygen intermediates, which induce NFB activation (73). Adenosine has been indicated as another trigger of the preconditioning response, as infusion of adenosine can evoke the response, probably through A1 receptor stimulation. Purines may induce activation of NFB (74,75), although this finding is controversial (76). Preconditioning of adenosine protected a human cardiomyocyte cell line via a p38 MAPK pathway (77), whereas adenosine A1 receptor stimulation could evoke delayed preconditioning in the intact rabbit via upregulation of the NFB-regulated manganese superoxide dismutase (78). Nitric oxide has been suggested as both a trigger and a mediator of the preconditioning response, and this has recently been reviewed by Bolli et al. (79). Nitric oxide donors activate myocardial NFB, and inhibition of NO during the preconditioning episodes abolishes the beneficial effects (79). The NO theory of preconditioning has recently been linked to the adenosine theory, as A1 receptor agonists could evoke preconditioning in wild-type mice but not in mice with targeted disruption of the inducible NO synthase gene (80).

Myocardial protection by NFB activation may be caused by induction of an NFB-regulated mediator, such as manganese superoxide disumutase as discussed above (78). Recently, both inducible cyclooxygenase (81) and inducible NO synthase (82) have been indicated as mediators of delayed preconditioing through studies in knockout mice, who, as opposed to the wild types, could not be protected by preconditioning. Myocardial protection by NFB activation could also be caused by a downregulation of the inflammatory response during reperfusion. Morgan et al. (71) found a reduced activation of NFB after sustained ischemia in hearts that had been subjected to preconditioning. Similarily, we found reduced activation of NFB during ischemia and reperfusion in hearts of rats that had been pretreated with hyperoxia, probably secondary to an increase of IB in hyperoxic hearts with induced protection (83). In human umbilical vein endothelial cells preconditioned by hydrogen peroxide, reduced upregulation of cytokines and leukocyte adhesion molecules after subsequent stimulation with TNF- was found (84). Heat shock proteins of the 70-kDa family, which are upregulated during preconditioning by other pathways, have been suggested as mediators of ischemic adaption (85). Heat shock proteins modulate AP-1 and NFB DNA binding activity (86,87) and might reduce NFB activation and thereby reduce inflammation during reperfusion. A last possible route of NFB-mediated cardioprotection is through the antiapoptotic effect of preconditioning. Preconditioning reduces apoptosis during reperfusion, which may be linked to an NFB-dependent increase of cardiac Bcl-2 (48,70).

	A role for NFB in atherosclerosis and unstable coronary syndromes

Top Abstract Activation of NF{kappa}B Cell biological effects of... NF{kappa}B in apoptosis NF{kappa}B in myocardial... NF{kappa}B in ischemic... A role for NF{kappa}B... NF{kappa}B in heart failure Summary References

 
Nuclear factor kappa-B may play a role in the development of atherosclerosis by transducing pathogenic stimulation to expression of genes that promote recruitment and activation of inflammatory cells in the plaque. The NFB-regulated inflammatory mediators such as cytokines, inducible NO synthase and leukocyte adhesion molecules have been detected in atherosclerotic lesions (88–90). Activated NFB has been indentified in macrophages, smooth muscle cells and endothelial cells in human atherosclerotic plaques but not in healthy vessels (91,92). Activation of NFB may occur after stimulation of lesional cells by pathogenically important factors such as reactive oxygen species involved in low-density lipoprotein oxidation and components of microorganisms such as Chlamydia pneumoniae (93). This notion is supported by the observation that mice deficient in NFB signaling exhibit reduced fatty-streak formation when fed a fatty diet (94).

Unstable coronary syndromes are currently believed to be caused by rupture of an atherosclerotic plaque due to local events, which may be of infectious, immunologic, or general inflammatory etiology (95,96). Plaques from patients with unstable coronary syndromes exhibit increased expression of several NFB-regulated genes, including tissue factor, an initiator of coagulation, the cytokines IL-1, TNF-, interferon- and IL-6 and inducible NO synthase (89,91,95–100). These patients have a general inflammatory response: the acute-phase reactant C-reactive protein is increased, as are soluble leukocyte adhesion molecules and markers of leukocyte activation (96,101–104). Ritchie (104) recently showed that NFB is activated in peripheral leukocytes from patients with unstable angina. Interestingly, it has lately been observed that pericardial fluid from patients with unstable angina obtained during open heart surgery induced apoptotic cell death in murine endothelial cells independently of Fas and TNF- (105). Apoptosis may be important in plaque activation by destabilizing the plaque cap (106). Whether the systemic response of unstable angina is a cause or a consequence of disease remains controversial. However, it is noteworthy that several proteolytic enzymes proposed to be instrumental for plaque rupture are transcriptionally regulated through NFB elements.

Unstable angina reduces morbidity and mortality of acute myocardial infarction, probably because of a preconditioning effect (107). We postulated that unstable angina would elicit a tissue response analogous to cardiac and remote preconditioning, and we assessed NFB activation in right atrial biopsies (108). Nuclear factor kappa-B was activated in nuclear extracts from unstable patients with recent or ongoing symptoms. Additionally, some of the protective proteins associated with delayed preconditioning, namely heat-shock protein 72 and endothelial NO synthase, were increased in atrial tissue from unstable patients (108). Paradoxically, unstable coronary syndromes increase the morbidity and mortality of coronary artery bypass grafting (109). It must be kept in mind in this context that unstable patients scheduled for acute coronary revascularization are a heterogenous group, where the time frame between onset of symptoms and the surgery may be far beyond the range of the time frame indicated for the preconditioning response (0 to 2 or 24 to 72 h).

Furthermore, open heart surgery represents a massive inflammatory trauma with systemic increases of pro-inflammatory cytokines, soluble leukocyte adhesion molecules, neutrophil activation and endotoxemia due to major surgery itself, extracorporeal circulation and cardiac ischemia-reperfusion (110). The inflammatory response to cardioplegia and reperfusion in patients with unstable angina is more severe than in stable patients, evidenced as increased myocardial gene expression of some NFB-regulated mediators during reperfusion (62). Thus, the role of NFB in unstable coronary syndromes is not clear, and it appears to be multifacilitated.

	NFB in heart failure

Top Abstract Activation of NF{kappa}B Cell biological effects of... NF{kappa}B in apoptosis NF{kappa}B in myocardial... NF{kappa}B in ischemic... A role for NF{kappa}B... NF{kappa}B in heart failure Summary References

 
Recent evidence has suggested that an inflammatory response participates in the development of heart failure, and NFB may also be of importance in this aspect of pathologies (111–116). Myocardial tissue from patients with heart failure of various etiologies exhibits activation of NFB (111) and increased expression of genes it regulates such as inducible cyclo-oxygenase, TNF-, inducible NO synthase and leukocyte adhesion molecules (111–116). The expression of NFB-regulated pro-inflammatory genes appears to be independent of etiology of failure but appears connected to the degree of disease (111–116). The human TLR-4 is not expressed in the normal heart but is expressed in remodeling murine myocardium and in patients with idiopathic dilated cardiomyopathy, indicating activation of innate immunity in the injured myocardium (117). Signaling to TLR-4 activation may be dependent on TLR-2 in myocytes as a response to oxidative stress (118). When either TLR-2 or TLR-4 was blocked, increased cytotoxicity was found, indicating that NFB is important for remodeling and repair of injured myocardium (117,118).

	Summary

Top Abstract Activation of NF{kappa}B Cell biological effects of... NF{kappa}B in apoptosis NF{kappa}B in myocardial... NF{kappa}B in ischemic... A role for NF{kappa}B... NF{kappa}B in heart failure Summary References

 
Research over recent years indicates that the transcription factor NFB may play a key role in the pathophysiology of myocardial ischemia-reperfusion injury, ischemic preconditioning, apoptosis, atherosclerosis, unstable coronary syndromes and heart failure. Although activation of NFB aggravates ischemic injury, it appears to trigger protection in preconditioning. This may be due to reduction of apoptosis, reduction of inflammation or upregulation of protective substances such as manganese superoxide dismutase, inducible cyclooxygenase and inducible NO synthase. Both systemic and cardiac activation of NFB have been found in unstable coronary syndromes, although the functional consequences are as yet undetermined. Thus, NFB may be a new therapeutic target for increased myocardial protection.

	Footnotes

 
This work is supported by the Swedish Medical Research Council (projects 6816 and 12665) and the Swedish Heart-Lung Foundation.

	References

Top Abstract Activation of NF{kappa}B Cell biological effects of... NF{kappa}B in apoptosis NF{kappa}B in myocardial... NF{kappa}B in ischemic... A role for NF{kappa}B... NF{kappa}B in heart failure Summary References

 

1. Barnes PJ, Adcock IM. NFB: a pivotal role in asthma and a new target for therapy. Trends Pharmacol Sci. 1997;18:46–50[Medline]
2. Chen F, Castranova V, Shi X, Demers LM. New insights into the role of nuclear factor-B, a ubiquitous transcription factor in the initiation of disease. Clin Chem. 1999;45:7–17[Abstract/Free Full Text]
3. Ghosh S, May MJ, Kopp EB. NF-B and REL proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998;16:225–260[CrossRef][Medline]
4. Thurberg BL, Collins T. The nuclear factor kappa-B/inhibitor of kappa-B autoregulatory system and antherosclerosis. Curr Opin Lipidol. 1998;9:387–396[CrossRef][Medline]
5. Li N, Karin M. Is NF-B the sensor of oxidative stress? FASEB J. 1999;13:1137–1143[Abstract/Free Full Text]
6. Li C, Browder W, Kao LR. Early activation of transcription factor NF-B during ischemia in perfused rat heart. Am J Physiol. 1999;276:H543–H552[Medline]
7. Li Y, Zhang W, Mantell LL, Kazzaz JA, Fein AM, Horowitz S. Nuclear factor-B is activated by hyperoxia but does not protect from cell death. J Biol Chem. 1997;272:20646–20649[Abstract/Free Full Text]
8. Chen ZJ, Parent L, Maniatis T. Site-specific phosphorylation of I-kappa-B-alpha by a novel ubiquitination-dependent protein kinase activity. Cell. 1996;84:853–862[CrossRef][Medline]
9. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M. A cytokine-responsive I-kappa-B kinase that activates the transcription factor NF-kappa-B. Nature. 1997;388:548–554[CrossRef][Medline]
10. Mercurio F, Zhu H, Murray BW, et al. IKK-1 and IKK-2: cytokine-activated I-kappa-B kinases essential for NF-kappa-B activation. Science. 1997;278:860–866[Abstract/Free Full Text]
11. Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M. The I-kappa-B kinase complex (IKK) contains two kinase subunits, IKK-alpha and IKK-beta, necessary for I-kappa-B phosphorylation and NF-kappa-B activation. Cell. 1997;91:243–252[CrossRef][Medline]
12. Yamaoka S, Courtois G, Bessia C, et al. Complementation cloning of NEMO, a component of the I-kappa-B kinase complex essential for NF-kappa-B activation. Cell. 1998;93:1231–1240[CrossRef][Medline]
13. Rothwarf DM, Zandi E, Natoli G, Karin M. IKK-gamma is an essential regulatory subunit of the I-kappa-B kinase complex. Nature. 1998;395:297–300[CrossRef][Medline]
14. Mercurio F, Murray BW, Shevchenko A, et al. I-kappa-B kinase (IKK)-associated protein I, a common component of the heterogeneous IKK complex. Mol Cell Biol. 1999;19:1526–1538[Abstract/Free Full Text]
15. Li Y, Kang J, Friedman J, et al. Identification of a cell protein (FIP-3) as a modulator of NF-kappaB activity and as a target of an adenovirus inhibitor of tumor necrosis factor-alpha–induced apoptosis. Proc Natl Acad Sci U S A. 1999;96:1042–1047[Abstract/Free Full Text]
16. Regnier CH, Song HY, Gao X, Goeddel DV, Cao Z, Rothe M. Identification and characterization of an I-kappa-B kinase. Cell. 1997;90:373–383[CrossRef][Medline]
17. Ling L, Cao Z, Goeddel DV. NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-176. Proc Natl Acad Sci U S A. 1998;95:3792–3797[Abstract/Free Full Text]
18. Lee FS, Peters RT, Dang LC, Maniatis T. MEKK1 activates both I-kappa-B kinase alpha and I-kappa-B kinase beta. Proc Natl Acad Sci U S A. 1998;95:9319–9324[Abstract/Free Full Text]
19. Karin M. The beginning of the end: I-kappa-B kinase (IKK) and NF-kappaB activation. J Biol Chem. 1999;274:27339–27342[Free Full Text]
20. Peters RT, Liao SM, Maniatis T. IKK-epsilon is part of a novel PMA-inducible Ikappa-B kinase complex. Mol Cell. 2000;5:513–522[CrossRef][Medline]
21. Shimada T, Kawai T, Takeda K, et al. IKK-i, a novel lipopolysaccharide-inducible kinase that is related to IkappaB kinases. Int Immunol. 1999;11:1357–1362[Abstract/Free Full Text]
22. Nomura F, Kawai T, Nakanishi K, Akira S. NF-kappaB activation through IKK-i-dependent I-TRAF/TANK phosphorylation. Genes Cells. 2000;5:191–202[Abstract]
23. Zwacka RM, Zhang Y, Zhou W, Halldorson J, Engelhardt JF. Ischemia/reperfusion injury in the liver of BALB/c mice activates AP-1 and nuclear factor-kB independently of IkB degradation. Hepatology. 1998;28:1022–1030[CrossRef][Medline]
24. Baeuerle PA. IB–NF-B Structures: at the interface of inflammation control. Cell. 1998;95:729–731[CrossRef][Medline]
25. Baldwin AS. The NF-B and IB proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649–681[CrossRef][Medline]
26. Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T. Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa-B and cytokine-inducible enhancers. FASEB J. 1995;9:899–909[Abstract]
27. Bevilacqua MP, Pober JS, Mendrick DL, Cotran RS, Gimbrone MA. Identification of an inducible endothelial-leukocyte adhesion molecule. Proc Natl Acad Sci U S A. 1987;84:9238–9242[Abstract/Free Full Text]
28. Geng YJ, Hansson GK, Holme E. Interferon- and tumor necrosis factor synergize to induce nitric oxide production and inhibit mitochondrial respiration in vascular smooth muscle cells. Circ Res. 1992;7:1268–1276
29. Lee E, Vaughan DE, Parikh SH, et al. Regulation of matrix metalloproteinases and plasminogen activator inhibitor-1 synthesis by plasminogen in cultured human vascular smooth muscle cells. Circ Res. 1996;78:44–49[Abstract/Free Full Text]
30. Libby P, Warner S, Friedman GB. Interleukin-1: a mitogen for human vascular smooth muscle cells that induces the release of growth-inhibitory prostanoids. J Clin Invest. 1988;81:487–498[Medline]
31. Loppnow H, Libby P. Adult human vascular endothelial cells express the IL-6 gene differentially in response to LPS or IL. Cell Immunol. 1989;122:493–503[CrossRef][Medline]
32. Loppnow H, Libby P. Proliferating or interleukin-1-activated human vascular smooth muscle cells secrete copious interleukin-6. J Clin Invest. 1990;85:731–738[Medline]
33. Pober JS, Cotran RS. Cytokines and endothelial cell biology. Physiol Rev. 1990;70:427–456[Free Full Text]
34. Warner S, Auger KR, Libby P. Interleukin-1 induces interleukin-1. II. Recombinant human interleukin-1 induces interleukin-1 production by adult human vascular endothelial cells. J Immunol. 1987;139:1911–1917[Abstract]
35. Akira S, Hirano T, Taga T, Kishimoto T. Biology of multifunctional cytokines: IL-6 and related molecules (IL-1 and TNF). FASEB J. 1990;4:2860–2867[Abstract]
36. Medzhitov R, Janeway CA. Innate immunity: the virtues of a nonclonal system of recognition. Cell. 1997;91:295–298[CrossRef][Medline]
37. Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature. 2000;406:782–787[CrossRef][Medline]
38. Beyaert R, Fiers W. Molecular mechanisms of tumor necrosis factor-induced cytotoxicity. What we do understand and what we do not. FEBS Lett. 1994;340:9–16[CrossRef][Medline]
39. Antwerp DJV, Martin SJ, Kafri T, Green DR, Verma IM. Suppression of TNF--induced apoptosis by NF-B. Science. 1996;274:787–789[Abstract/Free Full Text]
40. Beg AA, Sha WC, Bronson RT, Ghosh S, Baltimore D. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature. 1995;376:167–170[CrossRef][Medline]
41. Geng Y-J, Wu Q, Muszynski M, Hansson GK, Libby P. Apoptosis of vascular smooth muscle cells induced by in vitro stimulation with interferon-, tumor necrosis factor- and interleukin-1ß. Arterioscler Thromb Vasc Biol. 1996;16:19–27[Abstract/Free Full Text]
42. Lawrence R, Chang LJ, Siebenlist U, Bressler P, Sonenshein GE. Vascular smooth muscle cells express a constitutive NF-kappa B-like activity. J Biol Chem. 1994;269:28913–28918[Abstract/Free Full Text]
43. Erl W, Hansson GK, de Martin R, Draude G, Weber KS, Weber C. Nuclear factor-kappa-B regulates induction of apoptosis and inhibitor of apoptosis protein-1 expression in vascular smooth muscle cells. Circ Res. 1999;84:668–677[Abstract/Free Full Text]
44. Erl W, Weber C, Hansson GK. Pyrrolidine dithiocarbamate-induced apoptosis depends on cell type, density, and the presence of Cu(2+) and Zn(2+). Am J Physiol. 2000;278:C1116–C1125
45. Beg AA, Baltimore D. An essential role for NF-B in preventing TNF--induced cell death. Science. 1996;274:782–784[Abstract/Free Full Text]
46. Liston P, Roy N, Tamai K, et al. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature. 1996;379:349–353[CrossRef][Medline]
47. Stehlik C, de Martin R, Kumabashiri I, Schmid JA, Binder BR, Lipp J. Nuclear factor (NF)-kappa-B–regulated X-chromosome-linked iap gene expression protects endothelial cells from tumor necrosis factor-alpha-induced apoptosis. J Exp Med. 1998;188:211–216[Abstract/Free Full Text]
48. Maulik N, Goswami S, Galang N, Das DK. Differential regulation of Bcl-2, AP-1, and NFB on cardiomyocyte apoptosis during myocardial ischemic stress adaption. FEBS Lett. 1999;443:331–336[CrossRef][Medline]
49. de Moissac D, Zheng H, Kirschenbaum LA. Linkage of the BH4 domain of Bcl-2 and the nuclear factor-B signaling pathway for suppression of apoptosis. J Biol Chem. 1999;274:29505–29509[Abstract/Free Full Text]
50. Martinon F, Holler N, Richard C, Tschopp J. Activation of a pro-apoptotic amplification loop through inhibition of NF-kappaB-dependent survival signals by caspase-mediated inactivation of RIP. FEBS Lett. 2000;468:134–136[CrossRef][Medline]
51. Schneider A, Martin-Villalba A, Weih F, et al. NF-kappaB is activated and promotes cell death in focal cerebral ischemia. Nat Med. 1999;5:554–559[CrossRef][Medline]
52. Li Q, Van Antwerp D, Mercurio F, Lee KF, Verma IM. Severe liver degeneration in mice lacking the IkappaB kinase-2 gene. Science. 1999;284:321–325[Abstract/Free Full Text]
53. Li Q, Lu Q, Hwang JY, et al. IKK1-deficient mice exhibit abnormal development of skin and skeleton. Genes Dev. 1999;13:1322–1328[Abstract/Free Full Text]
54. Tanaka M, Fuentes ME, Yamaguchi K, et al. Embryonic lethality, liver degeneration, and impaired NF-kappa-B activation in IKK-beta-deficient mice. Immunity. 1999;10:421–429[CrossRef][Medline]
55. Geng YJ, Petersson AS, Wennmalm , Hansson GK. Cytokine-induced expression of nitric oxide synthase results in nitrosylation of heme and nonheme iron proteins in vascular smooth muscle cells. Exp Cell Res. 1994;214:418–428[CrossRef][Medline]
56. Bond M, Fabunmi RP, Baker AH, Newby AC. Synergistic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: an absolute requirement for transcription factor NF-kappa B. FEBS Lett. 1998;435:29–34[CrossRef][Medline]
57. Peng H-B, Libby P, Liao JK. Induction and stabilization of IB by nitric oxide mediates inhibition of NF-B. J Biol Chem. 1995;270:14214–14219[Abstract/Free Full Text]
58. Shin WS, Hong YH, Peng HB, Decaterina R, Libby P, Liao JK. Nitric oxide attenuates vascular smooth muscle cell activation by interferon-gamma—the role of constitutive NF-Kappa-B activity. J Biol Chem. 1996;271:11317–11324[Abstract/Free Full Text]
59. Li C, Browder W, Kao RL. Early activation of transcription factor NF-kB during ischemia in perfused rat heart. Am J Physiol. 1999;276:H543–H552[Medline]
60. Chandrasekar B, Freeman GL. Induction of nuclear factor kB and activation protein-1 in postischemic myocardium. FEBS Lett. 1997;401:30–34[CrossRef][Medline]
61. Shimizu N, Yoshiyama M, Omura T, et al. Activation of mitogen-activated protein kinases and activator protein-1 in myocardial infarction in rats. Cardiovasc Res. 1998;38:116–124[Abstract/Free Full Text]
62. Valen G, Paulsson G, Vaage J. Induction of inflammatory mediators during reperfusion of the human heart. Ann Thorac Surg. 2001;71:226–232[Abstract/Free Full Text]
63. Gumina RJ, Newman PJ, Kenny D, Warltier DC, Gross GJ. The leukocyte cell adhesion cascade and its role in myocardial ischemia-reperfusion injury. Basic Res Cardiol. 1997;92:201–213[CrossRef][Medline]
64. Cain BS, Harken AH, Meldrum DR. Therapeutic strategies to reduce TNF-–mediated cardiac contractile depression following ischemia and reperfusion. J Mol Cell Cardiol. 1999;31:931–947[CrossRef][Medline]
65. Ono K, Matsumori A, Furukawa Y, et al. Prevention of myocardial reperfusion injury in rats by an antibody against monocyte chemotactic and activating factor/monocyte chemoattractant protein-1. Lab Invest. 1999;79:195–203[Medline]
66. Morishita R, Sugimoto T, Aoki M, et al. In vivo transfection of cis element "decoy" against nuclear factor-B binding site prevents myocardial infarction. Nat Med. 1997;3:894–899[CrossRef][Medline]
67. Sawa Y, Morishita R, Suzuki K, et al. A novel strategy for myocardial protection using in vivo transfection of cis element "Decoy" against NFB binding site. Circulation. 1997;96(Suppl II):II280–II285
68. Cooper M, Lindholm P, Peiper G, et al. Myocardial nuclear factor-B activity and nitric oxide production in rejecting cardiac allografts. Transplantation. 1998;66:838–844[CrossRef][Medline]
69. Xuan Y-T, Tang X-L, Banerjee S, et al. Nuclear factor-B plays an essential role in the late phase of ischemic preconditioning in conscious rabbits. Circ Res. 1999;84:1095–1109[Abstract/Free Full Text]
70. Maulik N, Sato M, Price BD, Das DK. An essential role of NFB in tyrosine kinase signaling of p38 MAP kinase regulation of myocardial adaptation to ischaemia. FEBS Lett. 1998;429:365–369[CrossRef][Medline]
71. Morgan EN, Boyle EM, Yun W, et al. An essential role for NFB in the cardioadaptive response to ischemia. Ann Thorac Surg. 1999;68:377–382[Abstract/Free Full Text]
72. Downey JM, Cohen MV. Signal transduction in ischemic preconditioning. Z Kardiol. 1995;4:77–86
73. Das DK, Maulik N, Sato M, Ray PS. Reactive oxygen species function as second messenger during ischemic preconditioing of heart. Mol Cell Biochem. 1999;196:59–67[CrossRef][Medline]
74. von Albertini M, Palmetshofer A, Kaczmarek E, et al. Extracellular ATP and ADP activate transcription factor NF-kappaB and induce endothelial cell apoptosis. Biochem Biophys Res Commun. 1998;248:822–829[CrossRef][Medline]
75. Nie Z, Mei Y, Ford M, et al. Oxidative stress increases adenosine A1 receptor expression by activating nuclear factor kappa-B. Mol Pharmacol. 1998;53:663–669[Abstract/Free Full Text]
76. Li C, Tuanzhu T, Liu L, Browder W, Kao RL. Adenosine prevents activation of transcription factor NF-B and enhances activator protein-1 binding activity in ischemic rat heart. Surgery. 2000;127:161–169[CrossRef][Medline]
77. Carroll R, Yellon DM. Delayed cardioprotection in a human cardiomyocyte-derived cell line: the role of adenosine, p38MAP kinase and mitochondrial KATP. Basic Res Cardiol. 2000;95:243–249[CrossRef][Medline]
78. Dana A, Jonassen AK, Yamashita N, Yellon DM. Adenosine A(1) receptor activation induces delayed preconditioning in rats mediated by manganese superoxide dismutase. Circulation. 2000;101:2841–2848[Abstract/Free Full Text]
79. Bolli R, Dawn B, Tang X-L, et al. The nitric oxide hypothesis of delayed preconditioning. Basic Res Cardiol. 1998;93:325–338[CrossRef][Medline]
80. Zhao T, Chelliah J, Levasseur JE, Kukreja RC. Inducible nitric oxide synthase mediates delayed myocardial protection induced by activation of adenosine A(1) receptors: evidence from gene-knockout animals. Circulation. 2000;102:902–907[Abstract/Free Full Text]
81. Shinmura K, Tang XL, Wang Y, et al. Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits. Proc Natl Acad Sci U S A. 2000;97:10197–10202[Abstract/Free Full Text]
82. Guo Y, Jones WK, Xuan Y-T, et al. The late phase of ischemic preconditioing is abrogated by targeted disruption of the inducible NO synthase gene. Proc Natl Acad Sci U S A. 1999;96:11507–11512[Abstract/Free Full Text]
83. Tähepôld P, Starkopf J, Dumitrescu A, Vaage J, Valen G. Hyperoxia elicits preconditioning through a NFB-dependent mechanism in the rat heart. Anesthesiology 2001. In Press.
84. Zahler S, Kupatt C, Becker BF. Endothelial preconditioning by transient oxidative stress reduces inflammatory responses of cultured endothelial cells to TNF-alpha. FASEB J. 2000;14:555–564[Abstract/Free Full Text]
85. Marber MS, Latchman DS, Walker JM, Yellon DM. Cardiac stress protein elevation 24 hours after brief ischaemia or heat stress is associated with resistance to myocardial infarction. Circulation. 1993;88:1264–1272[Abstract/Free Full Text]
86. Carter DA. Modulation of cellular AP-1 DNA binding activity by heat shock proteins. FEBS Lett. 1997;416:81–85[CrossRef][Medline]
87. Vayssier M, Favatier F, Pinot F, Bachelet M, Polla BS. Tobacco smoke induces coordinate activation of HSF and inhibition of NFkappaB in human monocytes: effects on TNFalpha release. Biochem Biophys Res Commun. 1998;252:249–256[CrossRef][Medline]
88. Barath P, Fishbein MC, Cao J, Berenson J, Helfant RH, Forrester JS. Tumor necrosis factor gene expression in human vascular intimal smooth muscle cells detected by in situ hybridization. Am J Pathol. 1990;137:503–509[Abstract]
89. Buttery LDK, Springall DR, Chester AH, et al. Inducible nitric oxide synthase is present within human atherosclerotic lesions and promotes the formation and activity of peroxynitrite. Lab Invest. 1996;75:77–85[Medline]
90. Frostegrd J, Ulfgren AK, Nyberg P, et al. Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis. 1999;145:33–43[CrossRef][Medline]
91. Bourcier T, Sukhova G, Libby P. The nuclear factor -B signaling pathway participates in dysregulation of vascular smooth muscle cells in vitro and in human atherosclerosis. J Biol Chem. 1997;272:15817–15824[Abstract/Free Full Text]
92. Brand K, Page S, Rogler G, et al. Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. J Clin Invest. 1996;97:1715–1722[Medline]
93. Kol A, Sukhova GK, Lichtman AH, Libby P. Chlamydial heat shock protein 60 localizes in human atheroma and regulates macrophage tumor necrosis factor-alpha and matrix metalloproteinase expression. Circulation. 1998;98:300–307[Abstract/Free Full Text]
94. Schreyer SA, Peschon JJ, LeBoeuf RC. Accelerated atherosclerosis in mice lacking tumor necrosis factor receptor p55. J Biol Chem. 1996;271:26174–26178[Abstract/Free Full Text]
95. Libby P. Molecular basis of the acute coronary syndromes. Circulation. 1995;91:2844–2850[Free Full Text]
96. Mehta JL, Saldeen TGP, Rand K. Interactive role of infection, inflammation and traditional risk factors in atherosclerosis and coronary artery disease. J Am Coll Cardiol. 1998;31:1217–1225[Abstract/Free Full Text]
97. Hansson GK, Holm J, Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol. 1989;135:169–175[Abstract]
98. Ikeda U, Ikeda M, Seino Y, Takahashi M, Kano S, Shimada K. Interleukin-6 gene transcripts are expressed in atherosclerotic lesions of genetically hyperlipidemic rabbits. Atherosclerosis. 1992;92:213–218[CrossRef][Medline]
99. Wilcox JN, Nelken NA, Coughlin S, Gordon D, Schall TJ. Local expression of inflammatory cytokines in human atherosclerotic plaques. J Atheroscler Thromb. 1994;(Suppl I):S10–S13
100. Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci U S A. 1989;86:2839–2843[Abstract/Free Full Text]
101. Biasucci LM, Vitelli A, Liuzzo G, et al. Elevated levels of interleukin-6 in unstable angina. Circulation. 1996;94:874–877[Abstract/Free Full Text]
102. Liuzzo G, Biasucci LM, Gallimore JR, et al. Prognostic value of C-reactive protein and plasma amyloid A protein in severe unstable angina. N Engl J Med. 1994;331:417–424[Abstract/Free Full Text]
103. Maseri A. Inflammation, atherosclerosis, and ischemic events—exploring the hidden side of the moon. N Engl J Med. 1997;336:1014–1016[Free Full Text]
104. Ritchie ME. Nuclear factor-B is selectively and markedly activated in humans with unstable angina pectoris. Circulation. 1998;98:1707–1713[Abstract/Free Full Text]
105. Iwakura A, Fujita M, Hasegawa K, et al. Pericardial fluid from patients with unstable angina induces vascular endothelial cell apoptosis. J Am Coll Cardiol. 2000;35:1785–1790[Abstract/Free Full Text]
106. Bauriedel G, Hutter R, Welsch U, Bach R, Sievert H, Luderitz B. Role of smooth muscle cell death in advanced coronary primary lesions: implications for plaque instability. Cardiovasc Res. 1999;41:480–488[Abstract/Free Full Text]
107. Kloner RA, Shook T, Przyklenk K, et al. Previous angina alters in-hospital outcome in TIMI-4. A clinical correlate to preconditioning? Circulation. 1995;91:37–47[Abstract/Free Full Text]
108. Valen G, Hansson GK, Dumitrescu A, Vaage J. Unstable angina activates myocardial heat shock protein 72, endothelial nitric oxide synthase, and transcription factors NFB and AP-1. Cardiovasc Res. 2000;47:49–56[Abstract/Free Full Text]
109. Iyer VS, Russell WJ, Leppard P, Craddock D. Mortality and myocardial infarction after coronary artery surgery. Med J Aust. 1993;159:166–170[Medline]
110. Royston D. The inflammatory response and extracorporeal circulation. J Cardiothorac Vasc Anesth. 1997;11:341–354[CrossRef][Medline]
111. Wong SC, Fukuchi M, Melnyk P, Rodger I, Giaid A. Induction of cyclooxygenase-2 and activation of nuclear factor kappaB in myocardium of patients with congestive heart failure. Circulation. 1998;98:100–103[Abstract/Free Full Text]
112. Kalra D, Baumgarten G, Dibbs Z, Seta Y, Sivasubramanian N, Mann DL. Nitric oxide provokes tumor necrosis factor-alpha expression in adult feline myocardium through a cGMP-dependent pathway. Circulation. 2000;102:1302–1307[Abstract/Free Full Text]
113. Fukuchi M, Hussain SN, Giaid A. Heterogenous expression and activity of endothelial and inducib