Prevention of cardiac hypertrophy and heart failure by silencing of NF-kappaB.
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.
Department of Molecular Cardiology, Lerner Research Institute, NB50, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA.
Sudhiranjan
S
Gupta
David
D
Young
Ratan K
RK
Maitra
Anasuya
A
Gupta
Zoran B
ZB
Popovic
Sandro L
SL
Yong
Anjuli
A
Mahajan
Qing
Q
Wang
Subha
S
Sen
D000375:Aging / Q000502:physiology; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000517:prevention & control*; D018450:Disease Progression; D005260:Female; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D020868:Gene Silencing; D006333:Heart Failure / Q000235:genetics / Q000517:prevention & control*; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism*; D009928:Organ Specificity / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014966:Xanthenes
D005456:Fluorescent Dyes; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014966:Xanthenes; C065700:myotrophin; C007293:DAPI; C034657:Texas red; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; D016650:Fluorescein-5-isothiocyanate