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miR‐126 at the dawn of angiogenic defect seen in PAH right ventricular failure.
Author(s) -
Potus Francois,
Graydon Colin,
Ryan Wong,
Michelakis Evangelos,
Provencher Steeve,
Bonnet Sébastien
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.630.8
Subject(s) - angiogenesis , matrigel , downregulation and upregulation , regulator , microrna , cancer research , medicine , chemistry , cardiology , biology , biochemistry , gene
Right ventricular (RV) failure is the most important predictor of both morbidity and mortality in pulmonary arterial hypertension (PAH). In PAH patients, hypertrophied RV is relatively ischemic, potentially because of suppressed angiogenesis. MicroRNAs (miRNAs) are important regulator of angiogenesis, especially miR‐126, which by inhibiting SPRED‐1, triggers the VEGF pathway and thus promoting angiogenesis. We hypothesized that specific miR‐126 downregulation in the RV promotes ischemia and triggers the transition from a compensated (CRV) to a decompensated (DRV) RV.Results We studied RV free wall tissues from humans with normal RV (NRV) functions, CRV and PAH (DRV), and rats with NRV and DRV. In both humans and rats, PAH DRV had decreased miR‐126 and microvessels density compared to NRV. Under the same conditions, miR‐126 were unchanged in the LV. In endothelial cells (EC) isolated from human RV, miR‐126 up‐regulation increased angiogenesis in a PAH DRV (matrigel assay), while downregulation of miR‐126 in EC from controls or CRV mimicked the PAH phenotype by decreasing angiogenesis. Artificial miR‐126 up‐regulation in PAH rat model improved RV functions, increased capillarity and decreased fibrosis specifically in RV, with no effect on PAP or lung vascular remodeling. Increasing miR‐126 levels in human PAH DRV endothelial cells also increased angiogenesis (matrigel assay). CONCLUSION We demonstrated that 1) exclusive RV downregulation of miR‐126 contributes to the ischemic status of the DRV; 2) in vivo up‐regulation of miR‐126 specifically improves RV functions. Thus, targeting miR‐126 represents a specific new avenue of investigation in preventing and reversing the failing RV in PAH.