Elevated levels of activin A in clinical and experimental pulmonary hypertension

Yndestad A, Larsen KO, Oie E, Ueland T, Smith C, Halvorsen B, Sjaastad I, Skjonsberg OH, Pedersen TM, Anfinsen OG, Damas JK, Christensen G, Aukrust P, Andreassen AK. Elevated levels of activin A in clinical and experimental pulmonary hypertension. J Appl Physiol 106: 1356-1364, 2009. First published February 5, 2009; doi:10.1152/japplphysiol.90719.2008.-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.