Impact of S-adenosylmethionine decarboxylase 1 on pulmonary vascular remodeling.
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.


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.
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.).
Friederike Christine
FC
Weisel
Christina
C
Kloepping
Alexandra
A
Pichl
Akylbek
A
Sydykov
Baktybek
B
Kojonazarov
Jochen
J
Wilhelm
Markus
M
Roth
Karen Marie
KM
Ridge
Kazuei
K
Igarashi
Kazuhiro
K
Nishimura
Wolfgang
W
Maison
Claudia
C
Wackendorff
Walter
W
Klepetko
Peter
P
Jaksch
Hossein Ardeschir
HA
Ghofrani
Friedrich
F
Grimminger
Werner
W
Seeger
Ralph Theo
RT
Schermuly
Norbert
N
Weissmann
Grazyna
G
Kwapiszewska
D012437:Adenosylmethionine Decarboxylase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D000860:Hypoxia / Q000150:complications; D008168:Lung / Q000098:blood supply*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*
C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D004815:Epidermal Growth Factor; D012437:Adenosylmethionine Decarboxylase
cell hypoxia; hypertension, pulmonary; muscle, smooth