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Nuclear Factor- (cid:1) B Decoy Infiltrating the Heart of the Matter in Inflammatory Heart Disease

Inflammation is part of the host response repertoire in defense against injury. Inflammatory processes play an important role in all the common cardiovascular diseases such as atherosclerosis, myocardial infarction, and heart failure. However, when the inflammatory process becomes uncontrolled, it can become part of the disease. This situation is best exemplified by inflammatory heart diseases such as viral or autoimmune myocarditis, where the immune system can be triggered by either external antigens such as a virus, or internal antigens such as myosin. The activated immune cells then undergo exuberant signal amplification, leading to clonal expansion of T lymphocytes and elaboration of cytokines, resulting in cell and matrix disruption and the phenotype of dilated cardiomyopathy.1,2 Giant cell myocarditis is an example of disproportionate immune response, including coalescence of macrophages into giant cells mixed with lymphocytes, with associated high mortality and no specific treatment. To understand the pathogenesis of giant cell myocarditis, an experimental model of autoimmune myocarditis (EAM) induced by myosin antigen mixed with adjuvant in the murine model has been previously developed.3,4 The myosin molecule contains a very specific epitope of approximately 8 amino acids in size that can also be mimicked by infectious agents, which is capable of triggering immune cell activation in an MHC-restricted context, leading to T cell–mediated destruction of the myocardium (Figure 1). This has been definitively demonstrated by humanized murine models in which the mouse MHC system has been substituted with the human homologues, and the disease can be perfectly reproduced with immunogens containing human myosin.5 The agents of destruction in this process include cytokines such as tumor necrosis factor (TNF)6 and nitric oxide produced in large quantities by the inducible nitric oxide synthase (iNOS).7 However, the immune system, being critical for host survival, is extremely redundant in its response. The question is whether there are additional central modulators of immune response that may be targets for therapeutic manipulation. Potential Role of NFB as Immune Regulator The activation of inflammatory response requires coordinated expression of a large number of effector systems to respond to external stress. The external stimuli, including infection, cytokine or neurohormone receptor activation, oxidative stress, matrix alterations, integrin binding, and cytoskeletal deformation, all converge through intracellular signaling pathways upon specific families of nuclear transcription factors, a prominent member being nuclear factorB (NFB).8 NFB is a dimeric transcription factor consisting of homodimers or heterodimers of Rel-related proteins. It normally resides in the cytoplasm, complexed with an inhibitor, I B, and is in an inactive form. Upon activation by external stimuli, the inflammatory signals converge on a set of regulatory control I B kinases known as the IKK complex.9 The IKK complexes can phosphorylate I B, leading to its ubiquitination and degradation by the proteosome (Figure 2). The liberated NFB then enters the nucleus, interacts with B elements in the promoter region of many inflammatory response genes, and activates their transcription. NFB is thus one of the central regulators of inflammatory response.10 Additional signaling events, including phosphorylation of NFB, hyperphosphorylation of IKK, and transcriptional regulation of I B and NFB, all modulate the level and duration of NFB activity. The classic antiinflammatory agent aspirin acts by binding IKK , thereby preventing the activation of NFB, similar to specific peptide strategies of NFB inhibition.11 The question is whether NFB also plays a central role in inflammatory heart disease, and whether it could represent a target for therapeutic modulation to alter the outcomes of the disease.