University of Oulu

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., 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. doi:10.1016/j.ymthe.2019.01.013

Systemic blockade of ACVR2B ligands protects myocardium from acute ischemia-reperfusion injury

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Author: Magga, Johanna1,2; Vainio, Laura1; Kilpiö, Teemu1;
Organizations: 1Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, 90220 Oulu, Finland
2Biocenter Oulu, University of Oulu, 90220 Oulu, Finland
3Neuromuscular Research Center, Biology of Physical Activity, Faculty of Sport and Health Sciences, University of Jyväskylä, 40014 Jyväskylä, Finland
4Department of Physiology, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland
5Medical Research Center Oulu, Oulu University Hospital and University of Oulu, 90220 Oulu, Finland
6Wihuri Research Institute and Translational Cancer Biology Program, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland
7Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
8Department of Medicine, University of Helsinki, 00029 Helsinki, Finland
9Department of Medicine, Helsinki University Hospital, 00029 Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.9 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2019062822297
Language: English
Published: Elsevier, 2019
Publish Date: 2019-06-28
Description:

Abstract

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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Series: Molecular therapy
ISSN: 1525-0016
ISSN-E: 1525-0024
ISSN-L: 1525-0016
Volume: 27
Issue: 3
Pages: 600 - 610
DOI: 10.1016/j.ymthe.2019.01.013
OADOI: https://oadoi.org/10.1016/j.ymthe.2019.01.013
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Subjects:
Funding: 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).
Academy of Finland Grant Number: 297094
268505
Detailed Information: 297094 (Academy of Finland Funding decision)
268505 (Academy of Finland Funding decision)
Copyright information: © 2019 The Author(s).This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
  https://creativecommons.org/licenses/by/4.0/