Downregulation of miR-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension
Background—Right ventricular (RV) failure is the most important factor of both morbidity and mortality in pulmonary arterial hypertension (PAH). Nonetheless, the underlying mechanisms resulting to the failing RV in PAH remain unknown. There is growing evidence that angiogenesis and microRNAs are involved in PAH-associated RV failure. We hypothesized that miR-126 downregulation decreases micro-vessel density and promotes the transition from a compensated to a decompensated RV in PAH.
Methods and Results—We studied RV free wall tissues from humans with normal RV (NRV n=17), compensated RV hypertrophy (CRVH n=8) and PAH patients with decompensated RV failure (DRV n=14). When compared to RV tissues from patients with CRVH, DRV patients had decreased miR-126 expression (qRT-PCR; p<0.01) and capillary density (CD31+ immunofluorescence; p<0.001) while LV tissues were not affected. MiR-126 downregulation was associated with increased SPRED-1, leading to decreased activation of RAF (P-RAF/RAF) and MAP kinase (P-MAP/MAP), thus inhibiting the VEGF pathway. In vitro, matrigel assay showed that miR-126 up-regulation increased angiogenesis of primary cultured endothelial cells from DRV patients. Furthermore, in vivo miR-126 up-regulation (mimic i.v injection) improved cardiac vascular density and function of monocrotaline-induced PAH animals.
Conclusions—RV failure in PAH is associated with a specific molecular signature within the RV, contributing to a decrease in RV vascular density and promoting the progression to RV failure. More importantly, miR-126 upregulation in the RV improves microvessel density and RV function in experimental PAH.
- Received March 11, 2015.
- Revision received June 23, 2015.
- Accepted July 6, 2015.