Is nuclear factor kappaB an attractive therapeutic target for treating cardiac hypertrophy?

Cardiovascular disease is the leading cause of morbidity and mortality in the United States. In most instances, heart failure is the final consequence of many underlying disease etiologies such as long-standing hypertension, coronary heart disease, valvular insufficiency, arrhythmia, viral myocarditis, and mutations in sarcomere-encoding genes. A compensatory enlargement of the myocardium, or hypertrophy, typically accompanies many of the predisposing insults discussed above and is a leading predictor for the development of more serious and life-threatening disease.1,2 Given the strong association between the presentation of pathological cardiac hypertrophy and a progressive deterioration in myocardial function, investigators have focused on understanding the molecular mechanisms that initiate the compensatory growth response or that precipitate the transition to heart failure. A number of signal transduction pathways are thought to play pivotal roles in mediating the hypertrophic growth of the myocardium in response to pathological stimuli.3 In this issue of Circulation , Cook et al4 focus their attention on the nuclear factor (NF)–κB signaling pathway as a potentially important intracellular mediator of cardiac hypertrophy. See p 664 NF-κB is a transcription factor that can directly regulate the expression of immediate-early genes and genes involved in the stress response following a variety of physiological or pathological stimuli. Traditionally, the NF-κB pathway has been implicated as a pivotal intracellular mediator of the inflammatory response associated with septic shock, ischemia-reperfusion injury, acute respiratory distress syndrome, viral-induced cytotoxic effects, and cytokine-mediated chronic disease states.5 These disease associations have made NF-κB an attractive target for pharmacological inhibition with the goal of preserving end organ function following acute injury or resulting from chronic inflammatory disorders. Recent studies by several investigators have also implicated NF-κB activation as a causal event in the cardiac hypertrophic response, as modeled in cultured cardiac myocytes.6–9 This linkage between NF-κB and myocyte …

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