Systemic blockade of ACVR2B ligands protects myocardium from acute ischemia-reperfusion injury
Magga, J., Vainio, L., Kilpiö, T., Hulmi, J., Taponen, S., Lin, R., Räsänen, M., Szabó, Z., Gao, E., Rahtu-Korpela, L., Alakoski, T., Ulvila, J., Laitinen, M., Pasternack, A., Koch, W. J., Alitalo, K., Kivelä, R., Ritvos, O., & Kerkelä, R. (2019). Systemic blockade of ACVR2B ligands protects myocardium from acute ischemia-reperfusion injury. Molecular Therapy, 27(3), 600-610. https://doi.org/10.1016/j.ymthe.2019.01.013
Published inMolecular Therapy
© 2019 The Author(s).
Activin A and myostatin, members of the transforming growth factor (TGF)-β superfamily of secreted factors, are potent negative regulators of muscle growth, but their contribution to myocardial ischemia-reperfusion (IR) injury is not known. The aim of this study was to investigate if activin 2B (ACVR2B) receptor ligands contribute to myocardial IR injury. Mice were treated with soluble ACVR2B decoy receptor (ACVR2B-Fc) and subjected to myocardial ischemia followed by reperfusion for 6 or 24 h. Systemic blockade of ACVR2B ligands by ACVR2B-Fc was protective against cardiac IR injury, as evidenced by reduced infarcted area, apoptosis, and autophagy and better preserved LV systolic function following IR. ACVR2B-Fc modified cardiac metabolism, LV mitochondrial respiration, as well as cardiac phenotype toward physiological hypertrophy. Similar to its protective role in IR injury in vivo, ACVR2B-Fc antagonized SMAD2 signaling and cell death in cardiomyocytes that were subjected to hypoxic stress. ACVR2B ligand myostatin was found to exacerbate hypoxic stress. In addition to acute cardioprotection in ischemia, ACVR2B-Fc provided beneficial effects on cardiac function in prolonged cardiac stress in cardiotoxicity model. By blocking myostatin, ACVR2B-Fc potentially reduces cardiomyocyte death and modifies cardiomyocyte metabolism for hypoxic conditions to protect the heart from IR injury. ...
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- Liikuntatieteiden tiedekunta 
Related funder(s)Academy of Finland
Funding program(s)Research post as Academy Research Fellow, AoF
Additional information about fundingWe thank Marja Arbelius, Sirpa Rutanen, and Kirsi Salo (University of Oulu) for excellent technical assistance. We also acknowledge Joni Degerman, Maria Arrano de Kivikko, and Nada Bechara-Hirvonen (Wihuri Research Institute, University of Helsinki) and Tuuli Nissinen (University of Jyväskylä) for excellent technical assistance. This work was supported by research funding from Academy of Finland grants 268505 (J.M.), 275922 (J.J.H.), and 297094 (R. Kerkelä); the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7/2007-2013 under REA grant 317250 (M.R.); the Emil Aaltonen Foundation (T.K.); and the Finnish Foundation for Cardiovascular Research (J.M., L.V., T.K., Z.S., R. Kerkelä). ...
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