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This Article Full Text Full Text (PDF) All Versions of this Article: 297/2/H627    most recent 00294.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Gupta, S. Articles by Sen, S. PubMed PubMed Citation Articles by Gupta, S. Articles by Sen, S.

Silencing the myotrophin gene by RNA interference leads to the regression of cardiac hypertrophy

Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio

Submitted 24 March 2009 ; accepted in final form 3 June 2009

Myotrophin-induced activation of NF-B 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-B 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-B. 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-B signaling components. Our data suggest that using RNA interference to silence the myotrophin gene prevents NF-B activation, associated with an attenuation of CH. This strategy could be an excellent therapeutic means for the treatment of CH and HF.

nuclear factor-B; heart failure