Impact of S-adenosylmethionine decarboxylase 1 on pulmonary vascular remodeling
Authors: Christina Kloepping
Norbert Weissmann
Akylbek Sydykov
Baktybek Kojonazarov
Markus Roth
Alexandra Pichl
Hossein Ardeschir Ghofrani
Grazyna Kwapiszewska
Kazuei Igarashi
Friedrich Grimminger
Werner Seeger
Claudia Wackendorff
Wolfgang Maison
Walter Klepetko
Ralph Theo Schermuly
Friederike Christine Weisel
Kazuhiro Nishimura
Peter Jaksch
Karen Marie Ridge
Jochen Wilhelm
Journal: Circulation (2014)
Discipline: CLINICAL MEDICINE
Keywords: cell hypoxia; hypertension, pulmonary; muscle, smooth.
Affiliations: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Lung Center, Justus-Liebig-University Giessen, Giessen, Germany (F.C.W., C.K., A.P., A.S., B.K., J.W., M.R., H.A.G., F.G., W.S., R.T.S., N.W., G.K.); Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, IL (K.M.R.); Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (K.I., K.N.); University of Hamburg, Pharmaceutical and Medicinal Chemistry, Hamburg, Germany (W.M., C.W.); Department of Cardiothoracic Surgery, University Hospital of Vienna, Vienna, Austria (W.K., P.J.); Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (W.S.); and Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria (G.K.).

Abstract:  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 Cγ1 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. 

Retracted: No

PubPeer comments:
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