title: MicroRNA-140 is elevated and mitofusin-1 is downregulated in the right ventricle of the Sugen5416/hypoxia/normoxia model of pulmonary arterial hypertension.
abstract: Heart failure, a major cause of morbidity and mortality in patients with pulmonary arterial hypertension (PAH), is an outcome of complex biochemical processes. In this study, we determined changes in microRNAs (miRs) in the right and left ventricles of normal and PAH rats. Using an unbiased quantitative miR microarray analysis, we found 1) miR-21-5p, miR-31-5 and 3p, miR-140-5 and 3p, miR-208b-3p, miR-221-3p, miR-222-3p, miR-702-3p, and miR-1298 were upregulated (>2-fold; P < 0.05) in the right ventricle (RV) of PAH compared with normal rats; 2) miR-31-5 and 3p, and miR-208b-3p were upregulated (>2-fold; P < 0.05) in the left ventricle plus septum (LV+S) of PAH compared with normal rats; 3) miR-187-5p, miR-208a-3p, and miR-877 were downregulated (>2-fold; P < 0.05) in the RV of PAH compared with normal rats; and 4) no miRs were up- or downregulated with >2-fold in LV+S compared with RV of PAH and normal. Upregulation of miR-140 and miR-31 in the hypertrophic RV was further confirmed by quantitative PCR. Interestingly, compared with control rats, expression of mitofusin-1 (MFN1), a mitochondrial fusion protein that regulates apoptosis, and which is a direct target of miR-140, was reduced in the RV relative to LV+S of PAH rats. We found a correlation between increased miR-140 and decreased MFN1 expression in the hypertrophic RV. Our results also demonstrated that upregulation of miR-140 and downregulation of MFN1 correlated with increased RV systolic pressure and hypertrophy. These results suggest that miR-140 and MFN1 play a role in the pathogenesis of PAH-associated RV dysfunction.
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York;
authors.forename: Sachindra Raj
authors.initials: SR
authors.lastname: Joshi
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York;
authors.forename: Vidhi
authors.initials: V
authors.lastname: Dhagia
authors.affiliation: Department of Pharmacology and Center for Lung Biology, University of South Alabama, College of Medicine, Mobile, Alabama; and.
authors.forename: Salina
authors.initials: S
authors.lastname: Gairhe
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York.
authors.forename: John G
authors.initials: JG
authors.lastname: Edwards
authors.affiliation: Department of Pharmacology and Center for Lung Biology, University of South Alabama, College of Medicine, Mobile, Alabama; and.
authors.forename: Ivan F
authors.initials: IF
authors.lastname: McMurtry
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York; s_gupte@nymc.edu.
authors.forename: Sachin A
authors.initials: SA
authors.lastname: Gupte
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D006352:Heart Ventricles / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism*; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D018497:Ventricular Dysfunction, Right / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; C580706:MIRN140 microRNA, rat; C569395:MIRN208 microRNA, rat; C576526:MIRN221 microRNA, rat; C568897:MIRN222 microRNA, rat; C570112:MIRN31 microRNA, rat; D008565:Membrane Proteins; C489709:Mfn1 protein, rat; D035683:MicroRNAs; D024101:Mitochondrial Proteins; C546082:mirn21 microRNA, rat
keywords: heart; heart failure; hypertension; hypertrophy; lungs; miR; pulmonary; rats