Abstract
BackgroundMyocardin (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.Methodology/Principal FindingsThe 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/SignificanceThese 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.
Highlights
Despite diagnostic and therapeutic advances in clinical cardiology, heart failure (HF), both systolic and diastolic, remains a leading cause of morbidity and mortality in developed countries
Neonatal piglets injected with Dox develop a cardiotoxic cardiomyopathy that rapidly progresses to diastolic dysfunction with elevated filling pressures and ECG abnormalities such as ST/T wave depression and lowvoltage QRS complexes
Myocd mRNA levels, measured by microarray followed by quantitative real-time RT-PCR (qPCR) analyses, were 2-3-fold higher in failing versus non-failing left ventricular (LV) myocardium, whereas srf expression levels remained unchanged (Fig. 2A)
Summary
Despite diagnostic and therapeutic advances in clinical cardiology, heart failure (HF), both systolic and diastolic, remains a leading cause of morbidity and mortality in developed countries. A recent trend, based on a gene expression topology of the developing and diseased heart, has resulted in the re-interpretation of pathological ventricular remodeling in terms of rearrangement of key gene regulatory networks and downstream signaling pathways that are imbalanced, attenuated, or abnormally activated in failing myocardium [1,2,3,4,5]. After birth mutant mice with a conditionally inactivated myocd gene develop dilated cardiomyopathy accompanied by impaired cardiomyocyte structural organization and severely depressed systolic function. The results suggest that in fetal mouse heart myocd is required for functional differentiation of ventricular cardiomyocytes. 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). The molecular and functional consequences of myocd upregulation in HF are still unclear
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