04 February 2019 by Junichi Omura

Long Non-coding RNA H19 a new signaling hub in the Pathogenesis of Right Ventricular Failure associated with Pulmonary Arterial Hypertension

Background:

Right ventricular failure (RVF) is the major prognostic factor in pulmonary arterial hypertension (PAH). Nonetheless, RVF remained understudied. A better understanding of the molecular mechanisms accounting for the transition from a compensated (preserve cardiac output) RV hypertrophy (CRVH) to a decompensated (decrease cardiac output) RV hypertrophy (DRVH) is needed. The LncRNA H19 and its encoded miR-675 have been implicated in both hypertrophy and fibrosis 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, CRVH patients (Cardiac index, CI > 2.2) and DRVH patients (DRVH, PAH patients that died from RVF), that H19 and miR-675 were specifically up-regulated (p<0.001, n=7-12/group) in DRVH. By in situ hybridization we demonstrated that H19 upregulation in DRVH occurs in cardiomyocytes and cardiac fibroblasts and that upregulation of H19 positively correlates with RV hypertrophy and fibrosis and inversely correlates with RV functions. Interestingly H19/miR-675 up-regulation was RV specific as no change was seen in either the LV or lung of DRVH patients. Similar results were observed in the monocrotaline rat model.
In 70 PAH patients, plasma levels of H19 were up-regulated (p<0.001) and correlated with PAH severity (pulmonary vascular resistance, CI and pro-BNP) and prognosis. Mechanistically, we demonstrated that the up-regulation of H19 is associated with reduced CamKII-δ (excitation/contraction), HDAC4 (hypertrophy), Mitofusin 2 (metabolism) and increased CTGF (fibrosis) which were previously reported as H19 or miR-675 direct-targets and implicated in heart failure.

Conclusions:

We demonstrated that H19/miR-675 axis is implicated in the transition from CRVH to DRVH in human RVF. Given its RV specificity, circulating H19 represents an attractive biomarker of RV function in PAH patients. The therapeutic value of H19 remains to be established. 

 

About the author


profile picture of Junichi Omura

Junichi Omura

doctor

Laval university

Czech Republic

Key Contributors

Junichi Omura 1, Karima Habbout 1, Sandra Martineau 1, Sandra Breuils-Bonnet 1, Valérie Nadeau 1, François Potus 2, Stephen L. Archer 2, Roxane Paulin 1, Steeve Provencher 1, Olivier Boucherat 1, Sébastien Bonnet 1 : 1. Pulmonary Hypertension and Vascular Biology Research Group of Quebec Heart and Lung Institute, Laval University, Quebec, Canada 2. Department of Medicine, Queens University, Kingston, Ontario, Canada


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