Nuclear factor-kappaB (NF-kappaB) is a ubiquitous transcription factor that regulates various kinds of genes including inflammatory molecules, macrophage infiltration factors, cell adhesion molecules, and so forth, in various disease processes including cardiac hypertrophy and heart failure. Previously, we have demonstrated that activation of NF-kappaB was required in myotrophin-induced cardiac hypertrophy, in spontaneously hypertensive rats, and in dilated cardiomyopathy human hearts. Moreover, our recent study using the myotrophin-overexpressed transgenic mouse (Myo-Tg) model showed that short hairpin RNA-mediated knockdown of NF-kappaB significantly attenuated cardiac mass associated with improved cardiac function. Although it has been shown that NF-kappaB is substantially involved in cardiovascular remodeling, it is not clear whether the continuous blockade of NF-kappaB is effective in cardiovascular remodeling. To address this question, we took a genetic approach using IkappaB alpha triple mutant mice (3M) bred with Myo-Tg mice (a progressive hypertrophy/heart failure model). The double transgenic mice (Myo-3M) displayed an attenuated cardiac hypertrophy (9.8+/-0.62 versus 5.4+/-0.34, p<0.001) and improved cardiac function associated with significant inhibition of the NF-kappaB signaling cascade, hypertrophy marker gene expression, and inflammatory and macrophage gene expression at 24 weeks of age compared to Myo-Tg mice. NF-kappaB-targeted gene array profiling displayed several important genes that were significantly downregulated in Myo-3M mice compared to Myo-Tg mice. Furthermore, Myo-3M did not show any changes of apoptotic gene expression, indicating that significant inhibition of NF-kappaB activation reduces further proinflammatory reactions without affecting susceptibility to apoptosis. Therefore, development of therapeutic strategies targeting NF-kappaB may provide an effective approach to prevent adverse cardiac pathophysiological consequences.