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Elevated levels of activin A in clinical and experimental pulmonary hypertension

¹Research Institute for Internal Medicine, Rikshospitalet University Hospital, ²Institute for Experimental Medical Research, Ullevål University Hospital, ³Department of Pulmonary Medicine, Ullevål University Hospital, ⁴Center for Heart Failure Research, ⁵Institute for Surgical Research, Rikshospitalet University Hospital, ⁶Medical Department, Diakonhjemmet Hospital, ⁷Department of Endocrinology, Rikshospitalet University Hospital, ⁸Department of Cardiology, Ullevål University Hospital, ⁹Department of Cardiology, and ¹⁰Section of Clinical Immunology and Infectious Diseases, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway

Submitted 4 June 2008 ; accepted in final form 2 February 2009

Activin A, a member of the transforming growth factor (TGF)-β 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-β 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.

growth factors; inflammation; pathogenesis