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Cardiovascular Research 2004 63(1):8-10; doi:10.1016/j.cardiores.2004.04.023
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Inhibition of the activation of nuclear factor kappa B to reduce myocardial reperfusion injury and infarct size

Christoph Thiemermann*

Centre for Experimental Medicine, Nephrology and Critical Care, William Harvey Research Institute, John-Vane Science Centre, Barts and the Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M6BQ, UK

*Tel.: +44-207-9826199l; fax: +44-207-2511685. Email address: c.thiemermann{at}qmul.ac.uk

Received 30 March 2004; revised 21 April 2004; accepted 22 April 2004

See article by Onai et al. [6] (pages 51–59) in this issue.

Nuclear factor kappa B (NF-{kappa}B) is a transcription factor that plays a pivotal role in the induction of genes involved in physiological processes as well as in the response to injury and inflammation. The process leading to the activation of NF-{kappa}B requires phosphorylation of an inhibitor of NF-{kappa}B (I{kappa}B) by I{kappa}B kinase (IKK), resulting in degradation of I{kappa}B by the 26S proteasome. This allows the translocation of NF-{kappa}B from the cytosol to the nucleus, where the heterodimer binds to a response element in the promotor region of specific target genes. Activation of NF-{kappa}B induces gene programs leading to the transcription of factors that promote inflammation (i.e. adhesion molecules, cytokines and chemokines) but may also importantly contribute to tissue remodelling, the resolution of inflammation, and transcription of genes whose products have anti-inflammatory effects. Most notably, activation of NF-{kappa}B appears to play a significant role in the pathophysiology of endothelial dysfunction, unstable angina pectoris, acute myocardial infarction and heart failure [1–3]. In addition, prevention of the activation of NF-{kappa}B has been attributed to at least some of the beneficial effects of certain beta-blockers and statins [4 5].

In this issue of Cardiovascular Research, Onai et al. [6] report that a novel inhibitor of the activation of NF-{kappa}B (IMD-0354) reduces myocardial infarct size in the rat. Using an NF-{kappa}B–IKKβ reporter assay in human hepatoma cells transfected with a constitutively active mutant of IKKβ, the authors report that concentrations of less than 1 µM of IMD-0354 [N-(3,5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide] reduce the activity of NF-{kappa}B. In addition, IMD-0354 inhibited the phosphorylation of I{kappa}B{alpha} induced by TNF{alpha} in cultured neonatal cardiac myocytes of the rat as well as the associated formation of interleukin-1β and monocyte chemoattractant protein-1 (MCP-1). When compared to vehicle, administration of IMD-0354 at 5 min prior to the onset of reperfusion in Sprague–Dawley rats caused a dose-related reduction in the size of the infarct elicited by transient occlusion (30 min) and reperfusion (24 h) of the left anterior descending coronary artery. A maximum reduction in infarct size of approximately 60% was achieved with the highest dose of IMD-0354. The observed reduction in infarct size was associated with a reduction in the inflammatory response and resulted in improved left ventricular function [6]. The authors conclude that inhibition of the activation of NF-{kappa}B during reperfusion of ischemic myocardium reduces the degree of reperfusion injury by reducing the release of pro-inflammatory cytokines, chemokines, and adhesion molecules and, thus, an excessive inflammatory response occurring during the reperfusion period.

A number of different pharmacological approaches that also reduce the activation of NF-{kappa}B have also now been shown to reduce myocardial infarct size. Like IMD-0354, the cylopentenone prostaglandins PGA1 and 15-deoxy{Delta}12,14-PGJ2 (15d-PGJ2) attenuate the activation of the IKK complex [7,8] and reduce myocardial infarct size and the formation of the NF-{kappa}B-dependent gene products MCP-1, intercellular adhesion molecule-1 (ICAM-1), and inducible nitric oxide synthase (iNOS) in rat hearts subjected to regional myocardial (25 min) ischemia and reperfusion [9]. Similarly, the sesquiterpene lactone parthenolide reduces the activation of IKK caused by TNF{alpha} [10] as well as the activation of NF-{kappa}B and the degree of cardiac injury and inflammation caused by regional myocardial ischemia and reperfusion in the rat [11]. Inhibition of the activation of certain calpains reduce the degradation of I{kappa}B by the 26S proteasome [12] as well as the degree of myocardial stunning in the isolated-perfused ferret heart [13]. Moreover, the proteasome inhibitor PS-519 also reduces myocardial infarct size and the impairment in myocardial segment shortening as well as the activation of NF-{kappa}B during the early reperfusion period in a porcine model of myocardial infarction [14].

In their article, Onai and colleagues argue that the novel NF-{kappa}B inhibitor IMD-0354 may well be a more specific approach to inhibit the activation of NF-{kappa}B in vivo than some of the above-mentioned drugs, many of which have effects that are not related to the inhibition of NF-{kappa}B but that may contribute to the observed cardioprotective effects of these compounds. For instance, 15d-PGJ2 is a potent agonist of the nuclear receptor PPAR-{gamma} [8] and other selective PPAR-{gamma} agonists including rosiglitazone, ciglitazone, and pioglitazone that reduce myocardial infarct size [9]. Inhibitors of calpain activity may well protect the myocardium by preventing the detrimental effects of this calcium-activated cysteine protease. Parthenolide has to be administered in relatively large amounts, has a narrow therapeutic window, and inhibits the activities of 5-lipoxygenase and cyclooxygenase. Having said this, we cannot exclude that IMD-0354 exerts other (non-specific) effects, which may contribute to the observed cardioprotective effects of this inhibitor of IKK. For instance, benzamide and some of its analogues (i.e. 3-aminobenzamide) are inhibitors of the nuclear enzyme poly(ADP-ribose) polymerase (PARP), which is activated by DNA strand breaks caused by excessive generation of reactive oxygen species in the early reperfusion period of previously ischemic myocardium. Most notably, 3-aminobenzamide (and other PARP inhibitors) reduces myocardial reperfusion injury when given prior to the onset of reperfusion [15]. To gain a better understanding of the mechanism underlying the cardioprotective effect of IMD-0354, it would be useful to exclude that this benzamide analogue is an inhibitor of PARP activity. Although this is not entirely likely, the exclusion of this potential mechanism may be of particular importance, as the degree of NF-{kappa}B activation caused by ischemia–reperfusion is reduced in the heart of mice in which the gene for PARP-1 has been deleted [16].

In addition to pharmacological strategies, several molecular strategies have been designed to inhibit the activation of NF-{kappa}B in the heart. For instance, gene transfer (adenoviral vector) of I{kappa}B{alpha} reduces the degree of tissue injury and inflammation caused by regional myocardial ischemia and reperfusion in male C57BL/6 mice [17]. Similarly, retro-infusion of liposomal NF-{kappa}B decoy oligonucleotides into the ischemic myocardium (area at risk) reduces infarct size and improved the recovery of myocardial function in a porcine model of LAD-occlusion (for 60 min) and reperfusion (for up to 7 days) [18].

There is now growing evidence that NF-{kappa}B also plays an important role in the adaptation to ischemia–reperfusion injury [19]. A pronounced inflammatory response in the heart—like in other organs or tissues—is followed by an anti-inflammatory response, which plays a pivotal role in the resolution of inflammation. The activation of the redox-sensitive transcription factor NF-{kappa}B not only helps to initiate the inflammation caused by ischemia–reperfusion, but also to orchestrate the subsequent anti-inflammatory response. Thus, it is not surprising that activation of NF-{kappa}B contributes importantly to the delayed cardioprotective effects (i.e. second window of protection) caused by ischemia, endotoxin, or certain drugs. For instance, the delayed cardioprotective effect (24 h after drug administration) caused by an agonist of the adenosine A3 receptor is secondary to the activation of NF-{kappa}B in the heart, as it is attenuated by inhibition of NF-{kappa}B with pyrrolidinediethyldithiocarbamate (PDTC) and, more importantly, by targeted ablation of the p50 subunit of NF-{kappa}B. Similarly, the cardioprotective effect of an A3 receptor agonist was also lost after inhibition of the activity of inducible nitric oxide synthase (iNOS) and in iNOS knock-out mice, suggesting that the cardioprotective effect is mediated by nitric oxide [20].

Taken together, these findings suggest that inhibition of the activation of NF-{kappa}B—although useful to reduce the consequences of an acute ischemic episode—may be detrimental in the adaptation of the heart to repetitive episodes of ischemia followed by reperfusion. Thus, further studies are warranted to elucidate under which specific pathophysiological conditions the inhibition of NF-{kappa}B activation may be useful, and under which, detrimental.


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