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: Arne Yndestad, Karl-Otto Larsen, Erik Oie, Thor Ueland, Camilla Smith, Bente Halvorsen, Ivar Sjaastad, Ole Henning Skjønsberg, Turid M Pedersen, Ole-Gunnar Anfinsen, Jan Kristian Damås, Geir Christensen, Pål Aukrust, Arne K Andreassen
• Journal: Journal of applied physiology (Bethesda, Md. : 1985) (J Appl Physiol (1985)) Vol. 106 Issue 4 Pg. 1356-64 (Apr 2009) ISSN: 8750-7587 [Print] United States
• PMID: 19196915 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Endothelin-1
• Follistatin
• SMAD2 protein, human
• Smad2 Protein
• activin A
• Activins
• RNA

Topics

• Activins (metabolism)
• Adult
• Animals
• Blood Pressure (physiology)
• Blotting, Western
• Cell Proliferation
• Cytokines (biosynthesis)
• Endothelial Cells (metabolism)
• Endothelin-1 (biosynthesis, genetics)
• Female
• Follistatin (blood)
• Humans
• Hypertension, Pulmonary (metabolism, pathology)
• Immunoenzyme Techniques
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Myocytes, Smooth Muscle (metabolism, pathology)
• Phosphorylation
• Pulmonary Artery (cytology, metabolism, pathology)
• RNA (biosynthesis, genetics)
• Smad2 Protein (metabolism)
• Up-Regulation