title: Apolipoprotein A-I mimetic peptide 4F rescues pulmonary hypertension by inducing microRNA-193-3p.
abstract: BACKGROUND
  Pulmonary arterial hypertension is a chronic lung disease associated with severe pulmonary vascular changes. A pathogenic role of oxidized lipids such as hydroxyeicosatetraenoic and hydroxyoctadecadienoic acids is well established in vascular disease. Apolipoprotein A-I mimetic peptides, including 4F, have been reported to reduce levels of these oxidized lipids and improve vascular disease. However, the role of oxidized lipids in the progression of pulmonary arterial hypertension and the therapeutic action of 4F in pulmonary arterial hypertension are not well established.
  
  
  RESULTS
  We studied 2 different rodent models of pulmonary hypertension (PH): a monocrotaline rat model and a hypoxia mouse model. Plasma levels of hydroxyeicosatetraenoic and hydroxyoctadecadienoic acids were significantly elevated in PH. 4F treatment reduced these levels and rescued preexisting PH in both models. MicroRNA analysis revealed that microRNA-193-3p (miR193) was significantly downregulated in the lung tissue and serum from both patients with pulmonary arterial hypertension and rodents with PH. In vivo miR193 overexpression in the lungs rescued preexisting PH and resulted in downregulation of lipoxygenases and insulin-like growth factor-1 receptor. 4F restored PH-induced miR193 expression via transcription factor retinoid X receptor α.
  
  
  CONCLUSIONS
  These studies establish the importance of microRNAs as downstream effectors of an apolipoprotein A-I mimetic peptide in the rescue of PH and suggest that treatment with apolipoprotein A-I mimetic peptides or miR193 may have therapeutic value.
authors: From the Department of Anesthesiology, Division of Molecular Medicine (S.S., S.U., A.I., G.W., D. Mai, K.N., M.E.), Department of Medicine, Division of Cardiology (D. Meriwether, K.N., M.N., A.M.F., S.T.R.), Division of Pulmonary Critical Care Medicine (D.R.), Department of Molecular and Medical Pharmacology (S.T.R.), and Cardiovascular Research Laboratories (M.E.), David Geffen School of Medicine at University of California-Los Angeles; and Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada (F.P., S.B.-B., S.P., S.B.).
authors: Salil
authors: S
authors: Sharma
authors: From the Department of Anesthesiology, Division of Molecular Medicine (S.S., S.U., A.I., G.W., D. Mai, K.N., M.E.), Department of Medicine, Division of Cardiology (D. Meriwether, K.N., M.N., A.M.F., S.T.R.), Division of Pulmonary Critical Care Medicine (D.R.), Department of Molecular and Medical Pharmacology (S.T.R.), and Cardiovascular Research Laboratories (M.E.), David Geffen School of Medicine at University of California-Los Angeles; and Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada (F.P., S.B.-B., S.P., S.B.).
authors: Soban
authors: S
authors: Umar
authors: From the Department of Anesthesiology, Division of Molecular Medicine (S.S., S.U., A.I., G.W., D. Mai, K.N., M.E.), Department of Medicine, Division of Cardiology (D. Meriwether, K.N., M.N., A.M.F., S.T.R.), Division of Pulmonary Critical Care Medicine (D.R.), Department of Molecular and Medical Pharmacology (S.T.R.), and Cardiovascular Research Laboratories (M.E.), David Geffen School of Medicine at University of California-Los Angeles; and Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada (F.P., S.B.-B., S.P., S.B.).
authors: Francois
authors: F
authors: Potus
authors: From the Department of Anesthesiology, Division of Molecular Medicine (S.S., S.U., A.I., G.W., D. Mai, K.N., M.E.), Department of Medicine, Division of Cardiology (D. Meriwether, K.N., M.N., A.M.F., S.T.R.), Division of Pulmonary Critical Care Medicine (D.R.), Department of Molecular and Medical Pharmacology (S.T.R.), and Cardiovascular Research Laboratories (M.E.), David Geffen School of Medicine at University of California-Los Angeles; and Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada (F.P., S.B.-B., S.P., S.B.).
authors: Andrea
authors: A
authors: Iorga
authors: From the Department of Anesthesiology, Division of Molecular Medicine (S.S., S.U., A.I., G.W., D. Mai, K.N., M.E.), Department of Medicine, Division of Cardiology (D. Meriwether, K.N., M.N., A.M.F., S.T.R.), Division of Pulmonary Critical Care Medicine (D.R.), Department of Molecular and Medical Pharmacology (S.T.R.), and Cardiovascular Research Laboratories (M.E.), David Geffen School of Medicine at University of California-Los Angeles; and Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada (F.P., S.B.-B., S.P., S.B.).
authors: Gabriel
authors: G
authors: Wong
authors: From the Department of Anesthesiology, Division of Molecular Medicine (S.S., S.U., A.I., G.W., D. Mai, K.N., M.E.), Department of Medicine, Division of Cardiology (D. Meriwether, K.N., M.N., A.M.F., S.T.R.), Division of Pulmonary Critical Care Medicine (D.R.), Department of Molecular and Medical Pharmacology (S.T.R.), and Cardiovascular Research Laboratories (M.E.), David Geffen School of Medicine at University of California-Los Angeles; and Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada (F.P., S.B.-B., S.P., S.B.).
authors: David
authors: D
authors: Meriwether
authors: From the Department of Anesthesiology, Division of Molecular Medicine (S.S., S.U., A.I., G.W., D. Mai, K.N., M.E.), Department of Medicine, Division of Cardiology (D. Meriwether, K.N., M.N., A.M.F., S.T.R.), Division of Pulmonary Critical Care Medicine (D.R.), Department of Molecular and Medical Pharmacology (S.T.R.), and Cardiovascular Research Laboratories (M.E.), David Geffen School of Medicine at University of California-Los Angeles; and Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada (F.P., S.B.-B., S.P., S.B.).
authors: Sandra
authors: S
authors: Breuils-Bonnet
authors: From the Department of Anesthesiology, Division of Molecular Medicine (S.S., S.U., A.I., G.W., D. Mai, K.N., M.E.), Department of Medicine, Division of Cardiology (D. Meriwether, K.N., M.N., A.M.F., S.T.R.), Division of Pulmonary Critical Care Medicine (D.R.), Department of Molecular and Medical Pharmacology (S.T.R.), and Cardiovascular Research Laboratories (M.E.), David Geffen School of Medicine at University of California-Los Angeles; and Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada (F.P., S.B.-B., S.P., S.B.).
authors: Denise
authors: D
authors: Mai
authors: From the Department of Anesthesiology, Division of Molecular Medicine (S.S., S.U., A.I., G.W., D. Mai, K.N., M.E.), Department of Medicine, Division of Cardiology (D. Meriwether, K.N., M.N., A.M.F., S.T.R.), Division of Pulmonary Critical Care Medicine (D.R.), Department of Molecular and Medical Pharmacology (S.T.R.), and Cardiovascular Research Laboratories (M.E.), David Geffen School of Medicine at University of California-Los Angeles; and Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada (F.P., S.B.-B., S.P., S.B.).
authors: Kaveh
authors: K
authors: Navab
authors: From the Department of Anesthesiology, Division of Molecular Medicine (S.S., S.U., A.I., G.W., D. Mai, K.N., M.E.), Department of Medicine, Division of Cardiology (D. Meriwether, K.N., M.N., A.M.F., S.T.R.), Division of Pulmonary Critical Care Medicine (D.R.), Department of Molecular and Medical Pharmacology (S.T.R.), and Cardiovascular Research Laboratories (M.E.), David Geffen School of Medicine at University of California-Los Angeles; and Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada (F.P., S.B.-B., S.P., S.B.).
authors: David
authors: D
authors: Ross
authors: From the Department of Anesthesiology, Division of Molecular Medicine (S.S., S.U., A.I., G.W., D. Mai, K.N., M.E.), Department of Medicine, Division of Cardiology (D. Meriwether, K.N., M.N., A.M.F., S.T.R.), Division of Pulmonary Critical Care Medicine (D.R.), Department of Molecular and Medical Pharmacology (S.T.R.), and Cardiovascular Research Laboratories (M.E.), David Geffen School of Medicine at University of California-Los Angeles; and Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada (F.P., S.B.-B., S.P., S.B.).
authors: Mohamad
authors: M
authors: Navab
authors: From the Department of Anesthesiology, Division of Molecular Medicine (S.S., S.U., A.I., G.W., D. Mai, K.N., M.E.), Department of Medicine, Division of Cardiology (D. Meriwether, K.N., M.N., A.M.F., S.T.R.), Division of Pulmonary Critical Care Medicine (D.R.), Department of Molecular and Medical Pharmacology (S.T.R.), and Cardiovascular Research Laboratories (M.E.), David Geffen School of Medicine at University of California-Los Angeles; and Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada (F.P., S.B.-B., S.P., S.B.).
authors: Steeve
authors: S
authors: Provencher
authors: From the Department of Anesthesiology, Division of Molecular Medicine (S.S., S.U., A.I., G.W., D. Mai, K.N., M.E.), Department of Medicine, Division of Cardiology (D. Meriwether, K.N., M.N., A.M.F., S.T.R.), Division of Pulmonary Critical Care Medicine (D.R.), Department of Molecular and Medical Pharmacology (S.T.R.), and Cardiovascular Research Laboratories (M.E.), David Geffen School of Medicine at University of California-Los Angeles; and Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada (F.P., S.B.-B., S.P., S.B.).
authors: Alan M
authors: AM
authors: Fogelman
authors: From the Department of Anesthesiology, Division of Molecular Medicine (S.S., S.U., A.I., G.W., D. Mai, K.N., M.E.), Department of Medicine, Division of Cardiology (D. Meriwether, K.N., M.N., A.M.F., S.T.R.), Division of Pulmonary Critical Care Medicine (D.R.), Department of Molecular and Medical Pharmacology (S.T.R.), and Cardiovascular Research Laboratories (M.E.), David Geffen School of Medicine at University of California-Los Angeles; and Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada (F.P., S.B.-B., S.P., S.B.).
authors: Sébastien
authors: S
authors: Bonnet
authors: From the Department of Anesthesiology, Division of Molecular Medicine (S.S., S.U., A.I., G.W., D. Mai, K.N., M.E.), Department of Medicine, Division of Cardiology (D. Meriwether, K.N., M.N., A.M.F., S.T.R.), Division of Pulmonary Critical Care Medicine (D.R.), Department of Molecular and Medical Pharmacology (S.T.R.), and Cardiovascular Research Laboratories (M.E.), David Geffen School of Medicine at University of California-Los Angeles; and Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada (F.P., S.B.-B., S.P., S.B.).
authors: Srinivasa T
authors: ST
authors: Reddy
authors: From the Department of Anesthesiology, Division of Molecular Medicine (S.S., S.U., A.I., G.W., D. Mai, K.N., M.E.), Department of Medicine, Division of Cardiology (D. Meriwether, K.N., M.N., A.M.F., S.T.R.), Division of Pulmonary Critical Care Medicine (D.R.), Department of Molecular and Medical Pharmacology (S.T.R.), and Cardiovascular Research Laboratories (M.E.), David Geffen School of Medicine at University of California-Los Angeles; and Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada (F.P., S.B.-B., S.P., S.B.). meghbali@ucla.edu.
authors: Mansoureh
authors: M
authors: Eghbali
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000008:administration & dosage; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D010455:Peptides / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000235:genetics; D047490:Retinoid X Receptor alpha / Q000502:physiology
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; C568257:MIRN193 microRNA, mouse; D035683:MicroRNAs; C580762:Mirn193 microRNA, rat; D010455:Peptides; D047490:Retinoid X Receptor alpha; C582295:apolipoprotein A-I mimetic peptide 4F; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D017526:Receptor, IGF Type 1
keywords: apolipoprotein A-I mimetic peptide 4F; lipoproteins; miR-193, human; microRNAs; pulmonary arterial hypertension