Identification of Long Noncoding RNA H19 as a New Biomarker and Therapeutic Target in Right Ventricular Failure in Pulmonary Arterial Hypertension

Abstract

Background: Right ventricular (RV) function is the major determinant for both functional capacity and survival in patients with pulmonary arterial hypertension (PAH). Despite the recognized clinical importance of preserving RV function, the subcellular mechanisms that govern the transition from a compensated to a decompensated state remain poorly understood and as a consequence there are no clinically established treatments for RV failure and a paucity of clinically useful biomarkers. Accumulating evidence indicates that long noncoding RNAs are powerful regulators of cardiac development and disease. Nonetheless, their implication in adverse RV remodeling in PAH is unknown. Methods: Expression of the long noncoding RNA H19 was assessed by quantitative PCR in plasma and RV from patients categorized as control RV, compensated RV or decompensated RV based on clinical history and cardiac index. The impact of H19 suppression using GapmeR was explored in 2 rat models mimicking RV failure, namely the monocrotaline and pulmonary artery banding. Echocardiographic, hemodynamic, histological, and biochemical analyses were conducted. In vitro gain- and loss-of-function experiments were performed in rat cardiomyocytes. Results: We demonstrated that H19 is upregulated in decompensated RV from PAH patients and correlates with RV hypertrophy and fibrosis. Similar findings were observed in monocrotaline and pulmonary artery banding rats. We found that silencing H19 limits pathological RV hypertrophy, fibrosis and capillary rarefaction, thus preserving RV function in monocrotaline and pulmonary artery banding rats without affecting pulmonary vascular remodeling. This cardioprotective effect was accompanied by E2F transcription factor 1-mediated upregulation of enhancer of zeste homolog 2. In vitro, knockdown of H19 suppressed cardiomyocyte hypertrophy induced by phenylephrine, while its overexpression has the opposite effect. Finally, we demonstrated that circulating H19 levels in plasma discriminate PAH patients from controls, correlate with RV function and predict long-term survival in 2 independent idiopathic PAH cohorts. Moreover, H19 levels delineate subgroups of patients with differentiated prognosis when combined with the NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels or the risk score proposed by both REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) and the 2015 European Pulmonary Hypertension Guidelines. Conclusions: Our findings identify H19 as a new therapeutic target to impede the development of maladaptive RV remodeling and a promising biomarker of PAH severity and prognosis.

Implication of EZH2 in the Pro-Proliferative and Apoptosis-Resistant Phenotype of Pulmonary Artery Smooth Muscle Cells in PAH: A Transcriptomic and Proteomic Approach

“…Furthermore, no signal was detected in quadriceps muscle (data not shown), and no major change was seen in kidney and liver ( Figure S1). These data, combined with our previous finding showing that EZH2 is augmented in human compensated right ventricle (RV) but markedly decreased in decompensated RV from PAH patients [16], indicate that altered expression of EZH2 in PAH appears to be mainly restricted to the cardiopulmonary system.…”

“…Nevertheless, EZH2 loss-of-function targeted to RV cardiomyocytes was shown to induce cardiac hypertrophy and fibrosis [45]. In addition, we recently reported a dramatic downregulation of EZH2 in decompensated RV from PAH patients and animal models as well as an increased expression of EZH2 in animals presenting improved cardiac function secondary to therapeutic intervention [16]. These findings strongly suggest that interfering with EZH2 function may induce detrimental effects in the vulnerable PAH right ventricle and that specific delivery of EZH2 inhibitor to target cells should be envisioned.…”

“…Thus, EZH2 appears to rely on multiple cell context-dependent mechanisms to facilitate neoplastic transformation and sustain tumor growth. Although EZH2 was previously shown to be implicated in right ventricular dysfunction [16], its role in pulmonary vascular remodeling process in the setting of PAH remains largely unknown.…”

17β-estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin

“…Human RV free wall tissue was collected as described previously (21,64) from warm autopsies (<3 hours following death) or cardiac surgery. The RVF group was comprised of patients with congenital heart disease without LV involvement and patients with idiopathic or scleroderma-associated end-stage PAH (age 49.9±5.5 years; 70% female).…”

Recent advances on the roles of LncRNAs in cardiovascular disease

“…LncRNA H19 in plasma was identified to indicate the severity and prognosis of PAH(pulmonary arterial hypertension). 62 These results suggest that plasma level of lncRNAs can be used as marker to distinguish the malignant process of HF.…”