Targeted gene-silencing reveals the functional significance of myocardin signaling in the failing heart.
BACKGROUND
Myocardin (MYOCD), a potent transcriptional coactivator of smooth muscle (SM) and cardiac genes, is upregulated in failing myocardium in animal models and human end-stage heart failure (HF). However, the molecular and functional consequences of myocd upregulation in HF are still unclear.


RESULTS
The goal of the present study was to investigate if targeted inhibition of upregulated expression of myocd could influence failing heart gene expression and function. To this end, we used the doxorubicin (Dox)-induced diastolic HF (DHF) model in neonatal piglets, in which, as we show, not only myocd but also myocd-dependent SM-marker genes are highly activated in failing left ventricular (LV) myocardium. In this model, intra-myocardial delivery of short-hairpin RNAs, designed to target myocd variants expressed in porcine heart, leads on day 2 post-delivery to: (1) a decrease in the activated expression of myocd and myocd-dependent SM-marker genes in failing myocardium to levels seen in healthy control animals, (2) amelioration of impaired diastolic dysfunction, and (3) higher survival rates of DHF piglets. The posterior restoration of elevated myocd expression (on day 7 post-delivery) led to overexpression of myocd-dependent SM-marker genes in failing LV-myocardium that was associated with a return to altered diastolic function.


CONCLUSIONS
These data provide the first evidence that a moderate inhibition (e.g., normalization) of the activated MYOCD signaling in the diseased heart may be promising from a therapeutic point of view.
Developmental Biology Group, Institute of Health Sciences, University of La Coruña, La Coruña, Spain.
Mario
M
Torrado
Raquel
R
Iglesias
Alberto
A
Centeno
Eduardo
E
López
Alexander T
AT
Mikhailov
D000818:Animals; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D020868:Gene Silencing; D054144:Heart Failure, Diastolic / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020127:Recovery of Function / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D013552:Swine; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D000099251:Myocardin
D015415:Biomarkers; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D000099251:Myocardin