Prevention of Cardiac Hypertrophy and Heart Failure by Silencing of NF-κB

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