Impact of S-adenosylmethionine decarboxylase 1 on pulmonary vascular remodeling

Friederike Christine Weisel, Christina Kloepping, Alexandra Pichl, Akylbek Sydykov, Baktybek Kojonazarov, Jochen Wilhelm, Markus Roth, Karen Marie Ridge, Kazuei Igarashi, Kazuhiro Nishimura, Wolfgang Maison, Claudia Wackendorff, Walter Klepetko, Peter Jaksch, Hossein Ardeschir Ghofrani, Friedrich Grimminger, Werner Seeger, Ralph Theo Schermuly, Norbert Weissmann*, Grazyna Kwapiszewska

*Corresponding author for this work

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1510-1523
Number of pages14
JournalCirculation
Volume129
Issue number14
DOIs
Publication statusPublished - Apr 8 2014

    Fingerprint

Keywords

  • cell hypoxia
  • hypertension
  • muscle
  • pulmonary
  • smooth

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Weisel, F. C., Kloepping, C., Pichl, A., Sydykov, A., Kojonazarov, B., Wilhelm, J., ... Kwapiszewska, G. (2014). Impact of S-adenosylmethionine decarboxylase 1 on pulmonary vascular remodeling. Circulation, 129(14), 1510-1523. https://doi.org/10.1161/CIRCULATIONAHA.113.006402