Abstract 9518: Role for Mir-126 in Right Ventricle Failure in Pulmonary Arterial Hypertension
Rationale: Pulmonary arterial hypertension (PAH) is characterized by 1) pulmonary vascular lesions leading to increased pulmonary vascular resistance; 2) right ventricle (RV) microcirculation rarefaction contributing to its failure and 3) decrease skeletal muscle perfusion sustaining exercise intolerance. There is growing evidence that impaired angiogenesis could be a common denominator to this triad of abnormalities. An impaired endothelial function is recognized as the major trigger for PAH, although the mechanism remains unclear. MicroRNAs have emerged as major players in PAH pathogenesis. Thus we hypothesized that miR-126, an endothelial-specific pro-angiogenic microRNA is downregulated in PAH contributing to the pulmonary, RV and skeletal muscle abnormalities.
Methods and Results: By qRT-PCR, we showed that miR-126 is down regulated in lungs, RV and skeletal muscles of PAH patients (n=10 to 20; p<0.01) compared to non-PAH donors. This correlates with a reduction of microcirculation (CD31 staining; p<0.05) in the lungs, RV and skeletal muscles of PAH patients. In vitro, primary cultured endothelial cells (EC) isolated from non-PAH and PAH human lungs, RV and skeletal muscles showed a significant reduction of miR-126 compared to control-EC (n=5; p<0.05). Using matrigel, proliferation (Ki67) and apoptosis (TUNEL) assays, we showed that the decrease in miR-126 in PAH-EC decreases their angiogenesis capacity, proliferation and promotes apoptosis, all of which were restored upon miR-126 upregulation. Inversely, miR-126 inhibition in non-PAH-EC induces a PAH phenotype (n=5; p<0.05). ç Finally, a randomized, double-blind, placebo-controlled preclinical study revealed that miR-126 mimic i.v injection in rats with established PAH significantly improves (n=20; p<0.05) mean PA pressure, cardiac output, end-systolic and end-diastolic RV pressures and exercise tolerance (treadmill, p<0.05). These findings were associated with a greater lungs, RV and skeletal muscle perfusion.
Conclusions: We demonstrated for the first time that a single microRNA, miR-126, is responsible for the lungs, RV and skeletal muscle impairments seen in PAH patients, thus representing a novel and attractive therapeutic target for PAH.
Author Disclosures: F. potus: None. S. Malenfant: None. S. Breuils Bonnet: None. R. Paulin: None. P. Ferrero: None. E. michelakis: None. S. Provencher: None. S. Bonnet: Research Grant; Modest; Bayer. Other Research Support; Modest; actellion. Honoraria; Modest; Merck.
- © 2014 by American Heart Association, Inc.