Anne-Marie Koop

228 seems to be reversible to some extent, as lung transplantation often results in decreased pulmonary pressure, smaller RV and normalized septal shape. 17-19 The functional and structural differences between RV and LV highlight the fact that the current comprehensive knowledge on LV function and pathology cannot be directly applied to RV and that a better understanding of RV function and RV failure pathology is crucial in order to develop efficient and specific therapeutics for this cardiac condition. PAH is a complex disease with several etiologies and its remodelling can result from the interaction of different factors such as genetic background, epigenetic modifications and pathobiological environmental factors. 20 In the past decade, microRNAs emerged as small, non-coding RNAmolecules with the ability to repress or degrade mRNAs and thereby to regulate gene expression during various cellular processes, in many different tissues, including the myocardium. 21 Numerous studies have elucidated the role of microRNAs throughout cardiovascular development and remodelling. 22,23 Abnormal expression and dysregulation of numerous miRNAs have been associated to the onset and development of PAH. 24-27 As most studies focus on the vascular alterations and presently, little is known about the changes in microRNA expression patterns in the RV upon remodelling. Nevertheless, differences between the LV and RV may be explained by miR-expression patterns as the prevalence of specific miRs in the resting RV is quantitatively different from that in the LV, and this difference is maintained during afterload stress. 28 This implies that not only the remodelling process itself but also its regulation may be ventricle-specific. Although the number of studies unraveling such processes in the RV is scarce, a recent report suggested that downregulation of miR-208 is associated with deterioration of RV function, (on MCT-induced PH model. 29 In the damaged RV, nuclear receptor corepressor 1 (NCoR1), a target of miR-208, is activated leading to acetylation of the enhancer factor-2 (Mef2) promotor and thus inhibiting Mef2 expression. During the transition from RV hypertrophy to RV failure, Mef2 inhibition results in suppression of crucial metabolic, angiogenic and contractile adaptation of the RV to pressure overload, rapid RV decompensation and subsequent heart failure. 29 During LV remodelling, pathological hypertrophy is mediated by calcineurin activation and modulation of the calcineurin-nuclear factor of activated T-cells (NFAT) signaling activity, has shown to reduce LV hypertrophy and improve function. 30,31 Calcineurin activation has also reported to contribute to RV remodelling induced by pulmonary artery banding (PAB). 32 We have previously identified miR- 199b as a pro-hypertrophic microRNA during LV remodelling, induced by banding of the aorta, which induces calcineurin/NFAT-signaling activity leading to exaggerated LV remodelling and cardiac dysfunction. 34 Since we have successfully targeted the miR199b/calcineurin/NFAT pathway in experimentally induced left-sided heart