Anne-Marie Koop

9 311 on the relation between epigenetics, by means of BET-bromodomain inhibition, intracardiac lipid content and cardiac function. Molecular mechanisms of ventricular remodelling differ between the left and right ventricle RV adaptation concerns similar processes as LV adaptation, encompassing hypertrophy, angiogenesis and fibrosis. 41,42 Indeed, as part of characterization of the model, we identified these processes in our models of PAB and studied the potential underlying molecular mechanisms. These mechanisms appeared to be different in the RV compared to previously identified molecular mechanism in the LV ( chapter 6 and 7 ). Ventricular hypertrophy is accompanied with intracellular signaling cascades encompassing calcineurin and its downstream transcriptional effector nuclear factor activated T-cells (NFAT), in both the LV 43-46 and RV 47,48 ( chapter 2 , 4 , 6 and 7 ). In the stressed LV, NFAT is phosphorylated by dual-specificity tyrosine-phosphorylation regulated kinase 1a (Dyrk1a), which contributes to nuclear export and hereby halts cardiac remodelling. 49,50 MicroRNA 199b (miR-199b) has been identified as regulator of Dyrk1a expression in the pressure loaded LV. 51 In chapter 6 , we found that in the pressure loaded RV, similar as in the pressure loaded LV, the level of miR- 199b expression is inversely correlated to ventricular function. However, miR-199b expression level was not inversely correlated with Dyrk1a and no correlation with Rcan1.4, as representative of NFAT activation, was found. This indicates a distinct response mechanism of the pressure loaded RV compared to the LV, as has been indicated by Reddy and colleagues before. 51 In the latter study, microarray analysis showed RV specific alternations of microRNA’s upon increased pressure load. Especially microRNA’s known to be involved in apoptosis, energy availability and calciumhandling appeared to be RV specific. 52 The potentially diverse functions of microRNA’s in the different ventricles should be further determined. bHLH transcription factor heart and neural crest derivatives expressed transcript 2 (Hand2) is embryonically essential to give rise to a healthy RV. 54-56 However, in the LV, Hand 2 is also known to be involved in pathological remodelling in the LV. 53 In the current thesis, we demonstrate that Hand2 is not only essential for the RV during fetal life, but also during adulthood to resist conditions of increased RV pressure load. WhereHand2 in the LVacts on signaling cascades in hypertrophy, i.e. calcineurin-NFAT signalling, RNA sequencing of RV-tissue showed that Hand2 depletion will lead to downregulation of extracellular matrix, collagen organization and angiogenesis. Again, we hereby illustrated the distinct molecular mechanisms in the different ventricles in increased afterload conditions during adulthood.