Prevention of cardiac hypertrophy and heart failure by silencing of NF-kappaB.

• Abstract: Activation of the nuclear factor (NF)-kappaB 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-kappaB activity. Using this mouse model and an NF-kappaB-targeted gene array, we first determined the components of NF-kappaB signaling cascade and the NF-kappaB-linked genes that are expressed during the progression to cardiac hypertrophy and HF. Second, we explored the effects of inhibition of NF-kappaB signaling events by using a gene knockdown approach: RNA interference through delivery of a short hairpin RNA against NF-kappaB 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-kappaB activation and atrial natriuretic factor expression. Our data suggest, for the first time, that inhibition of NF-kappaB using direct gene delivery of sh-p65 RNA results in regression of cardiac hypertrophy. These data validate NF-kappaB as a therapeutic target to prevent hypertrophy/HF.
• Authors: Sudhiranjan Gupta, David Young, Ratan K Maitra, Anasuya Gupta, Zoran B Popovic, Sandro L Yong, Anjuli Mahajan, Qing Wang, Subha Sen (Affiliation: Department of Molecular Cardiology, Lerner Research Institute, NB50, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA.)
• Journal: Journal of molecular biology (J Mol Biol) Vol. 375 Issue 3 Pg. 637-49 (Jan 18 2008) ISSN: 1089-8638 [Electronic] England
• PMID: 18037434 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fluorescent Dyes
• Indoles
• Intercellular Signaling Peptides and Proteins
• NF-kappa B
• RNA, Messenger
• RNA, Small Interfering
• Rela protein, mouse
• Transcription Factor RelA
• Xanthenes
• myotrophin
• Fluorescein-5-isothiocyanate
• DAPI
• Texas red
• Ikbkb protein, mouse
• I-kappa B Kinase

Topics

• Aging (physiology)
• Animals
• Cardiomegaly (genetics, prevention & control)
• Disease Progression
• Female
• Fluorescein-5-isothiocyanate
• Fluorescent Dyes
• Gene Silencing
• Heart Failure (genetics, prevention & control)
• I-kappa B Kinase (genetics, metabolism)
• Indoles
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Male
• Mice
• Mice, Transgenic
• Microscopy, Fluorescence
• NF-kappa B (genetics, metabolism)
• Organ Specificity (genetics)
• RNA Interference
• RNA, Messenger (metabolism)
• RNA, Small Interfering (metabolism)
• Time Factors
• Transcription Factor RelA (genetics, metabolism)
• Xanthenes