Silencing the myotrophin gene by RNA interference leads to the regression of cardiac hypertrophy.
Am J Physiol Heart Circ Physiol
; 297(2): H627-36, 2009 Aug.
Article
em En
| MEDLINE
| ID: mdl-19502558
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Terapia Genética
/
Cardiomegalia
/
Miócitos Cardíacos
/
Peptídeos e Proteínas de Sinalização Intercelular
/
RNA Interferente Pequeno
Limite:
Animals
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article