Anne-Marie Koop

226 ABSTRACT Background and aims Despite its association with high mortality and morbidity, research on the pathophysiology of right ventricle (RV) failure has remained behind in regard to the left ventricle (LV). Similar to what happens in the LV, upon chronic pressure overload induced by pulmonary artery banding (PAB), calcineurin activation also contributes to RV remodelling. We have previously identified miR-199b as a pro-hypertrophic microRNA during LV remodelling that, in response to pressure overload, induces calcineurin/NFAT-signaling activity leading to exaggerated LV remodelling and cardiac dysfunction. In this study, we aimed at understanding the contribution of miR-199b to RV remodelling in response to pressure overload induced by pulmonary artery banding (PAB). Methods and results In the present study, wild-type (WT) and transgenic (TG) mice with cardiac-specific overexpression of miR-199b were subjected to six weeks of RV pressure overload induced by PAB. Echocardiographic and MRI derived hemodynamic parameters, and molecular remodelling were assessed for experimental groups and compared to sham-operated controls. Six weeks after PAB, levels of miR-199b increased in both WT and TG mice, resulting in significant differences in Nppb, Acta1 and Myh6 expression. The significantly higher miR-199b levels in the TG mice did not influence the Fulton index, but did result in higher relative cardiomyocyte surface area. RV function tended to be worse for TG mice, demonstrated by the inverse correlation for cardiac output and RV ejection fraction with miR-199b expression. Not only the RVwas affected by RV pressure overload, but also LV remodelling showed extensive differences at the molecular level between WT and TG mice. Differently, in the LV, miR-199b overexpression was accompanied by decreased Dyrk1a and increased Rcan1-4 expression as previously described in LV pressure overload. Although miR- 199b-induced calcineurin/NFAT activation mediates the inhibition of Dyrk1a in the LV, this does not apply for the pressure-loaded RV. Conclusions Increased expression levels of miR-199b in cardiomyocytes were associated with impairedRVfunctioninRVpressureoverload,whereasincreasedmiR-199bexpression withoutRVpressureoverloadwasnotsufficienttoworsenRVfunction.IntheLV,contrarily to the RV, upregulation of miR-199b in the LV leads Dyrk1a inhibition and activation of calcineurin/NFAT signaling, increasing LV susceptibility to RV stress. Altogether, these findings suggest a less prominent role for miR-199b in the RV compared to LV.