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Mir‐126 dependent alteration of angiogenesis contributes to right ventricle failure in pulmonary arterial hypertension (868.2)
Author(s) -
Potus Francois,
Graydon Colin,
Breuils Bonnet Sandra,
Paulin Roxane,
Michelakis Evangelos,
Provencher Steeve,
Bonnet sebastien
Publication year - 2014
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.28.1_supplement.868.2
Subject(s) - downregulation and upregulation , angiogenesis , cd31 , matrigel , ventricle , medicine , cardiology , pulmonary hypertension , neovascularization , cancer research , biology , biochemistry , gene
Right Ventricular Failure (RVF) is the most important predictor of both morbidity and mortality in pulmonary arterial hypertension (PAH). PAH hypertrophied RV is relatively ischemic, potentially because of angiogenesis defect. miR‐126 (pro‐angiogenic miRNA), triggers VEGF pathway by inhibiting SPRED‐1, have emerged as critical actor of angiogenesis. We hypothesized that specific miR‐126 downregulation will promote RV ischemia and the transition from compensated (CRV) to a decompensated (DRV) RV. We studied free RV wall tissue from humans with normal RV functions, CRV and PAH (DRV). As expected, compared to both control and CRV, DRV has decreased miR‐126 (qRT‐PCR) and microvessels density (CD31 immunofluorescence) 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 thus decreasing VEGF pathway. 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. 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.