Salil Sharma1, Soban Umar1, Francois Potus1, Andrea Iorga1, Gabriel Wong1, David Meriwether1, Sandra Breuils-Bonnet1, Denise Mai1, Kaveh Navab1, David Ross1, Mohamad Navab1, Steeve Provencher1, Alan M Fogelman1, Sébastien Bonnet1, Srinivasa T Reddy1, Mansoureh Eghbali2. 1. 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.). 2. 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.
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. METHODS AND 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.
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. METHODS AND RESULTS: We studied 2 different rodent models of pulmonary hypertension (PH): a monocrotalinerat model and a hypoxiamouse 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.
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