2. Academic Validation
  3. Systemic Blockade of ACVR2B Ligands Protects Myocardium from Acute Ischemia-Reperfusion Injury

Systemic Blockade of ACVR2B Ligands Protects Myocardium from Acute Ischemia-Reperfusion Injury

  • Mol Ther. 2019 Mar 6;27(3):600-610. doi: 10.1016/j.ymthe.2019.01.013.
Johanna Magga 1,  Laura Vainio 2,  Teemu Kilpiö 2,  Juha J Hulmi 3,  Saija Taponen 2,  Ruizhu Lin 4,  Markus Räsänen 5,  Zoltán Szabó 2,  Erhe Gao 6,  Lea Rahtu-Korpela 2,  Tarja Alakoski 2,  Johanna Ulvila 2,  Mika Laitinen 7,  Arja Pasternack 8,  Walter J Koch 6,  Kari Alitalo 5,  Riikka Kivelä 5,  Olli Ritvos 8,  Risto Kerkelä 4
Affiliations

Affiliations

  • 1 Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, 90220 Oulu, Finland; Biocenter Oulu, University of Oulu, 90220 Oulu, Finland. Electronic address: johanna.magga@oulu.fi.
  • 2 Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, 90220 Oulu, Finland.
  • 3 Neuromuscular Research Center, Biology of Physical Activity, Faculty of Sport and Health Sciences, University of Jyväskylä, 40014 Jyväskylä, Finland; Department of Physiology, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland.
  • 4 Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, 90220 Oulu, Finland; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, 90220 Oulu, Finland.
  • 5 Wihuri Research Institute and Translational Cancer Biology Program, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland.
  • 6 Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
  • 7 Department of Medicine, University of Helsinki, 00029 Helsinki, Finland; Department of Medicine, Helsinki University Hospital, 00029 Helsinki, Finland.
  • 8 Department of Physiology, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland.
PMID: 30765322 DOI: 10.1016/j.ymthe.2019.01.013
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.

Keywords

ACVR2B; activins; growth differentiation factors; ischemia-reperfusion injury.

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