title: Elevated levels of activin A in clinical and experimental pulmonary hypertension.
abstract: 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.
authors.affiliation: Research Institute for Internal Medicine, Rikshospitalet University Hospital, N-0027 Oslo, Norway. arne.yndestad@rr-research.no
authors.forename: Arne
authors.initials: A
authors.lastname: Yndestad
authors.forename: Karl-Otto
authors.initials: KO
authors.lastname: Larsen
authors.forename: Erik
authors.initials: E
authors.lastname: Oie
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
authors.forename: Camilla
authors.initials: C
authors.lastname: Smith
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.forename: Ole Henning
authors.initials: OH
authors.lastname: Skjønsberg
authors.forename: Turid M
authors.initials: TM
authors.lastname: Pedersen
authors.forename: Ole-Gunnar
authors.initials: OG
authors.lastname: Anfinsen
authors.forename: Jan Kristian
authors.initials: JK
authors.lastname: Damås
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Arne K
authors.initials: AK
authors.lastname: Andreassen
mesh_terms: 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
chemical_list: D016207:Cytokines; D019332:Endothelin-1; D038681:Follistatin; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C422405:activin A; D028341:Activins; D012313:RNA