Silencing the myotrophin gene by RNA interference leads to the regression of cardiac hypertrophy.
Myotrophin-induced activation of NF-kappaB has been shown to be associated with cardiac hypertrophy (CH) that progresses to heart failure (HF). In the present study, we examined the cause-and-effect relationship between myotrophin and NF-kappaB activation using small hairpin RNA (shRNA) against myotrophin both in vitro (using neonatal rat myocytes) and in vivo [using myotrophin transgenic (Myo-Tg) mice, which overexpress myotrophin in the heart, develop CH, and gradually progress to HF]. Among several lentiviral vectors expressing myotrophin shRNAs, L-sh-109 showed the best silencing effect at both the mRNA (155.3 +/- 5.9 vs. 32.5 +/- 5.5, P < 0.001) and protein levels associated with a significant reduction of atrial natriuretic factor (ANF) and NF-kappaB. In vivo, when L-sh-109 was delivered directly into the hearts of 10-wk-old Myo-Tg mice, we observed a significant regression of cardiac mass (8.0 vs. 5.7 mg/g, P < 0.001) and myotrophin gene expression (54.5% over untreated Myo-Tg mice, P < 0.001) associated with a reduction in ANF and NF-kappaB signaling components. Our data suggest that using RNA interference to silence the myotrophin gene prevents NF-kappaB activation, associated with an attenuation of CH. This strategy could be an excellent therapeutic means for the treatment of CH and HF.
Gupta
Sudhiranjan
S
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Maitra
Ratan
R
Young
Dave
D
Gupta
Anasuya
A
Sen
Subha
S
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D030161:Avian Proteins / Q000378:metabolism; D006332:Cardiomegaly / Q000503:physiopathology* / Q000628:therapy*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D015870:Gene Expression / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D006333:Heart Failure / Q000503:physiopathology / Q000628:therapy; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering
D030161:Avian Proteins; D016207:Cytokines; C071280:EMF-1 protein, Gallus gallus; D036341:Intercellular Signaling Peptides and Proteins; C000594638:MYH7 protein, rat; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C065700:myotrophin; D009320:Atrial Natriuretic Factor; D018995:Myosin Heavy Chains