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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2015     Display Documents

ID: 711884.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2015
Lysyl oxidases play a causal role in vascular remodeling in clinical and experimental pulmonary arterial hypertension
Authors:Nave, A. H.; Mizikova, I.; Niess, G.; Steenbock, H.; Reichenberger, F.; Talavera, M. L.; Veit, F.; Herold, S.; Mayer, K.; Vadasz, I.; Weissmann, N.; Seeger, W.; Brinckmann, J.; Morty, R. E.
Date of Publication (YYYY-MM-DD):2014-07
Title of Journal:Arterioscler Thromb Vasc Biol
Issue / Number:7
Start Page:1446
End Page:1458
Audience:Not Specified
Abstract / Description:OBJECTIVE: Pulmonary vascular remodeling, the pathological hallmark of pulmonary arterial hypertension, is attributed to proliferation, apoptosis resistance, and migration of vascular cells. A role of dysregulated matrix cross-linking and stability as a pathogenic mechanism has received little attention. We aimed to assess whether matrix cross-linking enzymes played a causal role in experimental pulmonary hypertension (PH). APPROACH AND RESULTS: All 5 lysyl oxidases were detected in concentric and plexiform vascular lesions of patients with idiopathic pulmonary arterial hypertension. Lox, LoxL1, LoxL2, and LoxL4 expression was elevated in lungs of patients with idiopathic pulmonary arterial hypertension, whereas LoxL2 and LoxL3 expression was elevated in laser-capture microdissected vascular lesions. Lox expression was hypoxia-responsive in pulmonary artery smooth muscle cells and adventitial fibroblasts, whereas LoxL1 and LoxL2 expression was hypoxia-responsive in adventitial fibroblasts. Lox expression was increased in lungs from hypoxia-exposed mice and in lungs and pulmonary artery smooth muscle cells of monocrotaline-treated rats, which developed PH. Pulmonary hypertensive mice exhibited increased muscularization and perturbed matrix structures in vessel walls of small pulmonary arteries. Hypoxia exposure led to increased collagen cross-linking, by dihydroxylysinonorleucine and hydroxylysinonorleucine cross-links. Administration of the lysyl oxidase inhibitor beta-aminopropionitrile attenuated the effect of hypoxia, limiting perturbations to right ventricular systolic pressure, right ventricular hypertrophy, and vessel muscularization and normalizing collagen cross-linking and vessel matrix architecture. CONCLUSIONS: Lysyl oxidases are dysregulated in clinical and experimental PH. Lysyl oxidases play a causal role in experimental PH and represent a candidate therapeutic target. Our proof-of-principle study demonstrated that modulation of lung matrix cross-linking can affect pulmonary vascular remodeling associated with PH.
Free Keywords:Adult; Aged, 80 and over; Animals; Anoxia/complications; Antihypertensive Agents/pharmacology; Case-Control Studies; Cell Hypoxia; Cells, Cultured; Collagen/metabolism; Disease Models, Animal; Elastin/metabolism; Enzyme Inhibitors/pharmacology; Familial Primary Pulmonary Hypertension; Female; Fibroblasts/enzymology/pathology; Gene Expression Regulation, Enzymologic; Humans; Hypertension, Pulmonary/drug therapy/*enzymology/etiology/genetics/pathology; Hypertrophy, Right Ventricular/enzymology/etiology/prevention & control; Isoenzymes; Male; Mice; Middle Aged; Monocrotaline; Muscle, Smooth, Vascular/enzymology/pathology; Myocytes, Smooth Muscle/enzymology/pathology; Protein-Lysine 6-Oxidase/antagonists & inhibitors/genetics/*metabolism; Pulmonary Artery/drug effects/*enzymology/pathology; RNA, Messenger/metabolism; Rats; Ventricular Dysfunction, Right/enzymology/etiology/physiopathology/prevention &; control; Young Adult; anoxia; extracellular matrix; hypertension; muscle; protein-lysine 6-oxidase; pulmonary; smooth
External Publication Status:published
Document Type:Article
Communicated by:MPI für Herz- und Lungenforschung
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:From the Division of Pulmonology, Department of Internal Medicine, University of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany (A.H.N., I.M., G.N., F.R., M.L.T., F.V., S.H., K.M., I.V., N.W., W.S., R.E.M.); Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (A.H.N., I.M., G.N., W.S., R.E.M.); and the Department of Dermatology (J.B.) and Institute of Virology and Cell Biology (J.B., H.S.), University of Lubeck, Lubeck, Germany. rory.morty@mpi-bn.mpg.de. %^ 1435822045
Identifiers:ISSN:1524-4636 (Electronic) 1079-5642 (Linking) %R 10.1161/ATVBAHA.114.303534
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