Portal de Periódicos da CAPES

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

2007; Elsevier BV; Volume: 375; Issue: 3 Linguagem: Inglês

10.1016/j.jmb.2007.10.006

1089-8638

Sudhiranjan Gupta, David Young, Ratan K. Maitra, Anasuya Das Gupta, Zoran Popović, Sandro L. Yong, Anjuli Mahajan, Qing Wang, Subha Sen,

RNA regulation and disease

Activation of the nuclear factor (NF)-κB 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-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. Second, we explored the effects of inhibition of NF-κB signaling events by using a gene knockdown approach: RNA interference through delivery of a short hairpin RNA against NF-κB 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-κB activation and atrial natriuretic factor 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. These data validate NF-κB as a therapeutic target to prevent hypertrophy/HF.