Abstract 13396: Downregulation of the Angiomir-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension
INTRODUCTION: Right Ventricular Failure (RVF) is the most important predictor of both morbidity and mortality in pulmonary arterial hypertension (PAH). Nonetheless, RVF remained understudied compared to the left ventricle (LV) and the reason for which the RV fails faster than the LV remains unknown. Many differences separate the 2 ventricles thus knowledge on LV cannot be extrapolated to the RV. In PAH patients, hypertrophied RV is relatively ischemic, potentially because of suppressed angiogenesis, explaining that hypertrophied RV muscle and its increased O2 requirements will fail at a point where an imbalance between O2 demand and delivery will take place. MicroRNAs (miRNAs) have emerged as important determinants of angiogenesis especially angio-miR-126, which by inhibiting SPRED-1, triggers VEGF pathway by increasing RAF/MAP signaling and thus promotes angiogenesis. We hypothesized that specific miR-126 downregulation will promote RV ischemia and the transition from compensated (CRV) to a decompensated (DRV) RV.
Methods/RESULTS: We studied free RV wall tissue from humans with normal RV functions (n=5), CRV (Fallot and pulmonary stenosis) (n=3) and PAH (DRV) (n=2), and rats with normal RV function, CRV and DRV (n=5 in each group). We used qRT-PCR to study the expression of miR-126 and CD31 immunofluorescence to measure heart microcirculation. As expected, compared to both control and CRV, DRV has decreased miR-126 (n=5; p<0.05) and microvessels density (n=5; p<0.05) creating an imbalance between O2 demand and delivery. Interestingly, under the same conditions, miR-126 expression did not fall in LV. miR-126 downregulation in DRV increases SPRED-1, decreasing RAF (P-RAF/RAF) and MAP kinase (P-MAP/MAP) thus decreasing VEGF pathway (p<0.05). Finally, in endothelial cells isolated from human RV, miR-126 up-regulation using mimic increased angiogenesis in a PAH model (matrigel assay) while downregulation of miR-126 (antagomir) in control or CRV mimicked PAH phenotype by decreasing angiogenesis.
CONCLUSION: We demonstrated for the first time that the specific RV downregulation of miR-126 contributes to ischemic status of the DRV. Targeting miR-126 represents a new avenue of investigation in preventing and reversing failing RV.
- © 2013 by American Heart Association, Inc.