title: Regulation and actions of activin A and follistatin in myocardial ischaemia-reperfusion injury.
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 2h 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 3h of hypoxia and 2h 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.
authors: Department of Surgery, Monash Medical Centre, Monash University, Clayton, Victoria 3168, Australia; MIMR-PHI Institute of Medical Research, Monash Medical Centre, Clayton, Victoria 3168, Australia. Electronic address: yi.chen@monash.edu.
authors: Yi
authors: Y
authors: Chen
authors: Department of Surgery, School of Medicine, University of Washington, Seattle, WA 98195-6410, USA.
authors: Christine
authors: C
authors: Rothnie
authors: Department of Surgery, School of Medicine, University of Washington, Seattle, WA 98195-6410, USA.
authors: Denise
authors: D
authors: Spring
authors: Department of Surgery, School of Medicine, University of Washington, Seattle, WA 98195-6410, USA.
authors: Edward
authors: E
authors: Verrier
authors: Heart Failure Research Group, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors: Kylie
authors: K
authors: Venardos
authors: Heart Failure Research Group, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors: David
authors: D
authors: Kaye
authors: MIMR-PHI Institute of Medical Research, Monash Medical Centre, Clayton, Victoria 3168, Australia; Epworth Research Institute, Epworth HealthCare, Richmond, Victoria 3121, Australia.
authors: David J
authors: DJ
authors: Phillips
authors: MIMR-PHI Institute of Medical Research, Monash Medical Centre, Clayton, Victoria 3168, Australia.
authors: Mark P
authors: MP
authors: Hedger
authors: Department of Surgery, Monash Medical Centre, Monash University, Clayton, Victoria 3168, Australia.
authors: Julian A
authors: JA
authors: Smith
mesh_terms: D028341:Activins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D038681:Follistatin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000378:metabolism
chemical_list: D038681:Follistatin; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051197:Toll-Like Receptor 4; C422405:activin A; D028341:Activins; D007770:L-Lactate Dehydrogenase
keywords: Activin; Follistatin; Heart; Ischaemia–reperfusion