Regulation and actions of activin A and follistatin in myocardial ischaemia–reperfusion injury |
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| Institution: | 1. Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Powstancow Wlkp. 72, 70-111 Szczecin, Poland;2. Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstancow Wlkp. 72, 70-111 Szczecin, Poland;3. Clinical Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, Powstancow Wlkp. 72, 70-111 Szczecin, Poland;4. Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, Powstancow Wlkp. 72, 70-111 Szczecin, Poland;1. Department of Cardiology, Bern University Hospital, Bern, Switzerland;2. Thoraxcenter, Erasmus University Hospital, Rotterdam, The Netherlands;3. Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland;4. Cardiac Catheterization Laboratory, Rigshospitalet, Copenhagen, Denmark;5. Department of Cardiology, Clinical Center of Serbia, Belgrade, Serbia;6. Bristol Heart Institute, Bristol, United Kingdom;7. Cardiology Department, Triemlispital, Zurich, Switzerland;8. Thoraxcentrum Twente, Twente University, Enschede, The Netherlands;9. Division of Cardiology, University Hospital, Geneva, Switzerland;10. Cardiocentro, Lugano, Switzerland;11. Rabin Medical Center, Petach Tikva, Israel;12. Tel Aviv University, Tel Aviv, Israel;13. Herzzentrum Bodensee, Kreuzlingen, Switzerland;14. Clinical Trials Unit, Department of Clinical Research, University of Bern, Bern, Switzerland;15. Cardiology Department, University Hospital Zurich, Zurich, Switzerland;1. Department of Morphology, Institute of Biosciences of Botucatu, São Paulo State University, Botucatu, São Paulo, Brazil;2. Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil;1. Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China;2. Department of Cardiothoracic Surgery, First Hospital of Qiqihaer, Qiqihaer, China;3. Department of Geriatrics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China |
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| Abstract: | Activin A, a member of the transforming growth factor-β superfamily, is stimulated early in inflammation via the Toll-like receptor (TLR) 4 signalling pathway, which is also activated in myocardial ischaemia–reperfusion. Neutralising activin A by treatment with the activin-binding protein, follistatin, reduces inflammation and mortality in several disease models. This study assesses the regulation of activin A and follistatin in a murine myocardial ischaemia–reperfusion model and determines whether exogenous follistatin treatment is protective against injury. Myocardial activin A and follistatin protein levels were elevated following 30 min of ischaemia and 2 h of reperfusion in wild-type mice. Activin A, but not follistatin, gene expression was also up-regulated. Serum activin A did not change significantly, but serum follistatin decreased. These responses to ischaemia–reperfusion were absent in TLR4−/− mice. Pre-treatment with follistatin significantly reduced ischaemia–reperfusion induced myocardial infarction. In mouse neonatal cardiomyocyte cultures, activin A exacerbated, while follistatin reduced, cellular injury after 3 h of hypoxia and 2 h of re-oxygenation. Neither activin A nor follistatin affected hypoxia-reoxygenation induced reactive oxygen species production by these cells. However, activin A reduced cardiomyocyte mitochondrial membrane potential, and follistatin treatment ameliorated the effect of hypoxia-reoxygenation on cardiomyocyte mitochondrial membrane potential. Taken together, these data indicate that myocardial ischaemia–reperfusion, through activation of TLR4 signalling, stimulates local production of activin A, which damages cardiomyocytes independently of increased reactive oxygen species. Blocking activin action by exogenous follistatin reduces this damage. |
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| Keywords: | Activin Follistatin Ischaemia–reperfusion Heart |
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