Background: Right ventricular failure (RVF) is a major adverse prognostic factor in pulmonary arterial hypertension (PAH). Recent omics analyses have demonstrated the deregulation of several long non-coding RNAs (LncRNAs) in heart failure, but their role in RVF remains unknown. The LncRNA H19 and its encoded miR-675 have been implicated in both hypertrophic and fibrotic processes (2 features of RVF) but never been studied in RVF.
Methods and Results: By qRT-PCR, we showed in human RV biopsies obtained from control donors, patients with compensated RV hypertrophy (cRV, cardiac index > 2.2) and decompensated RV (dRV, PAH patients died from RVF), that H19/miR-675 were specifically up-regulated in dRV (p<0.001, n=10-12/group) and correlated with cardiomyocyte hypertrophy and cardiac fibrosis. H19/miR-675 up-regulation was RV specific as no change was seen in either the LV or lung of PAH patients. Similar findings were noted in the monocrotaline (MCT) and the pulmonary artery banding (PAB) rat models of RVF, in which H19 expression inversely (p<0.001) correlated with RV function, as evaluated by echocardiography and right heart catheterization; and positively (p<0.001) with cardiomyocyte hypertrophy and cardiac fibrosis on histology. Knockdown of H19 using GapmeR improved RV function and reduced cardiomyocyte hypertrophy and cardiac fibrosis in MCT & PAB rats. Mechanistically, reduced expression of H19 was associated with upregulation of the epigenetic regulator EZH2, an established suppressor of cardiac hypertrophy and fibrosis. In vitro, inhibition of H19 suppressed phenylephrine (PE)-induced hypertrophy in both RV neonatal rat cardiomyocytes and H9C2 and upregulated EZH2. In contrast, forced expression of H19 using adenoviral vector induced cell hypertrophy. Consistent with these findings, EZH2 inhibition using siRNA induced cardiomyocyte hypertrophy under basal conditions whereas its overexpression prevented PE-induced hypertrophy.
Conclusions: Our findings identify H19 as a new therapeutic target for the prevention of the transition from cRV to dRV in PAH.