Elevated levels of activin A in clinical and experimental pulmonary hypertension.
Activin A, a member of the transforming growth factor (TGF)-beta superfamily, is involved in regulation of tissue remodeling and inflammation. Herein, we wanted to explore a role for activin A in pulmonary hypertension (PH). Circulating levels of activin A and its binding protein follistatin were measured in patients with PH (n = 47) and control subjects (n = 14). To investigate synthesis and localization of pulmonary activin A, we utilized an experimental model of hypoxia-induced PH. In mouse lungs, we also explored signaling pathways that can be activated by activin A, such as phosphorylation of Smads, which are mediators of TGF-beta signaling. Possible pathophysiological mechanisms initiated by activin A were explored by exposing pulmonary arterial smooth muscle cells in culture to this cytokine. Elevated levels of activin A and follistatin were found in patients with PH, and activin A levels were significantly related to mortality. Immunohistochemistry of lung autopsies from PH patients and lungs with experimental PH localized activin A primarily to alveolar macrophages and bronchial epithelial cells. Mice with PH exhibited increased pulmonary levels of mRNA for activin A and follistatin in the lungs, and also elevated pulmonary levels of phosphorylated Smad2. Finally, we found that activin A increased proliferation and induced gene expression of endothelin-1 and plasminogen activator inhibitor-1 in pulmonary artery smooth muscle cells, mediators that could contribute to vascular remodeling. Our findings in both clinical and experimental studies suggest a role for activin A in the development of various types of PH.
Yndestad
Arne
A
Research Institute for Internal Medicine, Rikshospitalet University Hospital, N-0027 Oslo, Norway. arne.yndestad@rr-research.no
Larsen
Karl-Otto
KO
Oie
Erik
E
Ueland
Thor
T
Smith
Camilla
C
Halvorsen
Bente
B
Sjaastad
Ivar
I
Skjønsberg
Ole Henning
OH
Pedersen
Turid M
TM
Anfinsen
Ole-Gunnar
OG
Damås
Jan Kristian
JK
Christensen
Geir
G
Aukrust
Pål
P
Andreassen
Arne K
AK
D028341:Activins / Q000378:metabolism*; D000328:Adult; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D042783:Endothelial Cells / Q000378:metabolism; D019332:Endothelin-1 / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D038681:Follistatin / Q000097:blood; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051899:Smad2 Protein / Q000378:metabolism; D015854:Up-Regulation
D016207:Cytokines; D019332:Endothelin-1; D038681:Follistatin; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C422405:activin A; D028341:Activins; D012313:RNA