title: Role of miR206 in genistein-induced rescue of pulmonary hypertension in monocrotaline model.
abstract: Pulmonary hypertension (PH) is a progressive lung disease associated with proliferation of smooth muscle cells and constriction of lung microvasculature, leading to increased pulmonary arterial pressure, right ventricular failure, and death. We have previously shown that genistein rescues preexisting established PH by significantly improving lung and heart function. (Matori H, Umar S, Nadadur RD, Sharma S, Partow-Navid R, Afkhami M, Amjedi M, Eghbali M. Hypertension 60: 425-430, 2012). Here, we have examined the role of microRNAs (miRs) in the rescue action of genistein in monocrotaline (MCT)-induced PH in rats. Our miR microarray analysis on the lung samples from control, PH, and genistein-rescue group revealed that miR206, which was robustly upregulated to ∼11-fold by PH, was completely normalized to control levels by genistein treatment. Next, we examined whether knockdown of miR206 could reverse preexisting established PH. PH was induced in male rats by 60 mg/kg of MCT, and rats received three intratracheal doses of either miR206 antagomir (10 mg/kg body wt) or scrambled miR control at days 17, 21, and 26. Knockdown of miR206 resulted in significant improvement in the cardiopulmonary function, as right ventricular pressure was significantly reduced to 38.6 ± 3.61 mmHg from 61.2 ± 5.4 mmHg in PH, and right ventricular hypertrophy index was decreased to 0.35 ± 0.04 from 0.59 ± 0.037 in PH. Knockdown of miR206 reversed PH-induced pulmonary vascular remodeling in vivo and was associated with restoration of PH-induced loss of capillaries in the lungs and induction of vascular endothelial growth factor A expression. In conclusion, miR206 antagomir therapy improves cardiopulmonary function and structure and rescues preexisting severe PH in MCT rat model possibly by stimulating angiogenesis in the lung.
authors.affiliation: Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and.
authors.forename: Salil
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and.
authors.forename: Soban
authors.initials: S
authors.lastname: Umar
authors.affiliation: Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and.
authors.forename: Alexander
authors.initials: A
authors.lastname: Centala
authors.affiliation: Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California meghbali@ucla.edu.
authors.forename: Mansoureh
authors.initials: M
authors.lastname: Eghbali
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000627:therapeutic use*; D000818:Animals; D002196:Capillaries / Q000473:pathology; D004562:Electrocardiography; D055785:Gene Knockdown Techniques; D019833:Genistein / Q000494:pharmacology / Q000627:therapeutic use*; D006334:Heart Function Tests; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy*; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000503:physiopathology; D008168:Lung / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics*; D016686:Monocrotaline; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012129:Respiratory Function Tests; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: D043925:Angiogenesis Inducing Agents; D035683:MicroRNAs; D042461:Vascular Endothelial Growth Factor A; C522220:mirn206 microRNA, rat; C467498:vascular endothelial growth factor A, rat; D016686:Monocrotaline; D019833:Genistein
keywords: angiogenesis; genistein; microRNA; pulmonary hypertension; right heart failure