In vivo forced expression of myocardin in ventricular myocardium transiently impairs systolic performance in early neonatal pig heart

Abstract

[Abstract] The aim of this study was to determine the effects of forced expression of myocd-A in the left ventricular (LV) myocardium on cardiac performance in early neonatal piglets. LV transfection with the gene for homeodomain only protein (hop), an antagonist of myocd-mediated activities, was also performed. Gene delivery was performed in 6-day-old piglets using a low-traumatic, catheter-based, video-assisted procedure developed by us for direct intra-myocardial injections of plasmid DNA into 3-4 target areas of the ventral LV free wall (LVFW). Two isoforms of porcine myocd were identified, cloned and characterized: the exon 11-lacking myocd-A and its larger exon 11-containig variant, myocd-B. In neonatal piglets, myocd-A seems to be a cardio-predominant isoform enriched in the LVFW/septum, whereas the myocd-B isoform is detected not only in the heart but also in various smooth muscle cell-containing tissues. Intramyocardial myocd-A gene delivery resulted in forced transgene expression in the target areas of the LVFW as compared to controls. On day 2 post-delivery, a marked decrease of LV-end systolic pressure values (an accepted marker for impaired LV function) was observed in myocd-A-transfected piglets as compared to hop-transfected and control groups. In addition, forced myocd-A expression in the LVFW caused abnormal ECG. A significant up-regulation of the gene for fetal-predominant muscle light chain 3F myosin was detected in myocd-A-transfected LVFWs harvested on day 2 post-delivery. Extended analysis on day 7 post-delivery revealed a drop decrease in myocd-A transgene expression in target LVFW regions which was correlated with normalization of the LV systolic parameters in experimented piglets.