Prevention of cardiac hypertrophy and heart failure by silencing of NF-κB

Activation of the nuclear factor (NF)-kappa B signaling pathway may be associated with the development of cardiac hypertrophy and its transition to heart failure (HF). The transgenic Myo-Tg mouse develops hypertrophy and HF as a result of overexpression. of myotrophin in the heart associated with an elevated level of NF-kappa B activity. Using this mouse model and an NF-kappa B-targeted gene array, we first determined the components of NF-kappa B signaling cascade and the NF-kappa B-linked genes that are expressed during the progression to cardiac hypertrophy and HE Second, we explored the effects of inhibition of NF-kappa B signaling events by using a gene knockdown approach: RNA interference through delivery of a short hairpin RNA against NF-kappa B p65 using a lentiviral vector (L-sh-p65). When the short hairpin RNA was delivered directly into the hearts of 10-week-old Myo-Tg mice, there was a significant regression of cardiac hypertrophy, associated with a significant reduction in NF-kappa B activation and atrial natriuretic factor expression. Our data suggest, for the first time, that inhibition of NF-kappa B using direct gene delivery of sh-p65 RNA results in regression of cardiac hypertrophy. These data validate NF-kappa B as a therapeutic target to prevent hypertrophy/HF. (c) 2007 Elsevier Ltd. All rights reserved.