NEMO Nuances NF-κB

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See related article, pages 133–144 Stress-induced adverse remodeling of the myocardium is a major mechanism leading to heart failure, a leading and rapidly escalating source of morbidity and mortality worldwide.1,2 As a result, much work is underway to dissect molecular mechanisms governing cardiac remodeling in hopes of identifying novel therapeutic targets. In recent years, much of this work has focused on the hypertrophic growth response of the cardiac myocyte. Initially adaptive, cardiac hypertrophy compensates for declines in cardiac performance and increases in wall stress; sustained hypertrophy, however, is a major risk factor for emergence of systolic dysfunction and clinical heart failure.3 On the bright side, numerous preclinical studies have demonstrated that abrogation of the hypertrophic response is well tolerated, and even beneficial.4 One potential target of therapy in the pathologically remodeled, hypertrophied heart is the transcription factor nuclear factor (NF)-κB. First discovered more than 20 years ago, NF-κB has been linked to numerous neurohormonal, pathophysiological, and stress stimuli responses, and it has been characterized most extensively in the immune system. In the heart, activation of NF-κB-dependent transcription has been detected in numerous disease contexts, including hypertrophy, ischemia/reperfusion injury, myocardial infarction, allograft rejection, myocarditis, apoptosis, and more.5,6 Within coronary vessels, NF-κB has been implicated in atherosclerosis and restenosis.5,6 However, parsing the specific role(s) of NF-κB in these diverse disease processes has been hampered by the embryonic lethality of inactivation of several NF-κB components.7–9 In heart, the NF-κB family of transcription factors comprises 4 members: p50, p52, p65, and RelB. All are capable of multimerization, forming either homo- or heterodimers, but the ubiquitously expressed p50 and p65 (herein termed NF-κB) are responsible for the majority of NF-κB binding activity in the myocardium. Activation of cytoplasmic NF-κB requires phosphorylation and subsequent proteasome-dependent degradation of its repressor, …