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



ID: 711847.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2015
Impact of S-adenosylmethionine decarboxylase 1 on pulmonary vascular remodeling
Authors:Weisel, F. C.; Kloepping, C.; Pichl, A.; Sydykov, A.; Kojonazarov, B.; Wilhelm, J.; Roth, M.; Ridge, K. M.; Igarashi, K.; Nishimura, K.; Maison, W.; Wackendorff, C.; Klepetko, W.; Jaksch, P.; Ghofrani, H. A.; Grimminger, F.; Seeger, W.; Schermuly, R. T.; Weissmann, N.; Kwapiszewska, G.
Date of Publication (YYYY-MM-DD):2014-04-08
Title of Journal:Circulation
Volume:129
Issue / Number:14
Start Page:1510
End Page:1523
Audience:Not Specified
Abstract / Description:BACKGROUND: Pulmonary hypertension (PH) is a life-threatening disease characterized by vascular remodeling and increased pulmonary vascular resistance. Chronic alveolar hypoxia in animals is often used to decipher pathways being regulated in PH. Here, we aimed to investigate whether chronic hypoxia-induced PH in mice can be reversed by reoxygenation and whether possible regression can be used to identify pathways activated during the reversal and development of PH by genome-wide screening. METHODS AND RESULTS: Mice exposed to chronic hypoxia (21 days, 10% O2) were reoxygenated for up to 42 days. Full reversal of PH during reoxygenation was evident by normalized right ventricular pressure, right heart hypertrophy, and muscularization of small pulmonary vessels. Microarray analysis from these mice revealed s-adenosylmethionine decarboxylase 1 (AMD-1) as one of the most downregulated genes. In situ hybridization localized AMD-1 in pulmonary vessels. AMD-1 silencing decreased the proliferation of pulmonary arterial smooth muscle cells and diminished phospholipase Cgamma1 phosphorylation. Compared with the respective controls, AMD-1 depletion by heterozygous in vivo knockout or pharmacological inhibition attenuated PH during chronic hypoxia. A detailed molecular approach including promoter analysis showed that AMD-1 could be regulated by early growth response 1, transcription factor, as a consequence of epidermal growth factor stimulation. Key findings from the animal model were confirmed in human idiopathic pulmonary arterial hypertension. CONCLUSIONS: Our study indicates that genome-wide screening in mice from a PH model in which full reversal of PH occurs can be useful to identify potential key candidates for the reversal and development of PH. Targeting AMD-1 may represent a promising strategy for PH therapy.
Free Keywords:Adenosylmethionine Decarboxylase/deficiency/genetics/*metabolism; Adult; Aged; Animals; Anoxia/complications; Apoptosis; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Down-Regulation; Early Growth Response Protein 1/metabolism; Epidermal Growth Factor/metabolism; Female; Humans; Hypertension, Pulmonary/etiology/*metabolism/*pathology; Lung/*blood supply; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microarray Analysis; Middle Aged; Muscle, Smooth, Vascular/drug effects/metabolism/pathology; Pulmonary Artery/*metabolism/*pathology; Signal Transduction/*physiology; cell hypoxia; hypertension, pulmonary; muscle, smooth
External Publication Status:published
Document Type:Article
Communicated by:MPI für Herz- und Lungenforschung
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:%^ 1435822045
Identifiers:ISSN:1524-4539 (Electronic) 0009-7322 (Linking) %R 10.1161/CIRCULATIONAHA.113.006402
URL:http://www.ncbi.nlm.nih.gov/pubmed/24470481
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