Magga 2019 Mol Ther
|Magga J, Vainio L, Kilpiö T, Hulmi JJ, Taponen S, Lin R, Räsänen M, Szabó Z, Gao E, Rahtu-Korpela L, Alakoski T, Ulvila J, Laitinen M, Pasternack A, Koch WJ, Alitalo K, Kivelä R, Ritvos O, Kerkelä R (2019) Systemic blockade of ACVR2B ligands protects myocardium from acute ischemia-reperfusion injury. Mol Ther [Epub ahead of print].|
Magga J, Vainio L, Kilpioe T, Hulmi JJ, Taponen S, Lin R, Raesaenen M, Szabo Z, Gao E, Rahtu-Korpela L, Alakoski T, Ulvila J, Laitinen M, Pasternack A, Koch WJ, Alitalo K, Kivelae R, Ritvos O, Kerkelae R (2019) Mol Ther
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: Activins, ACVR2B, Growth differentiation factors, Ischemia-reperfusion injury • Bioblast editor: Plangger M
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Cardiovascular, Myopathy Stress:Ischemia-reperfusion Organism: Mouse Tissue;cell: Heart Preparation: Homogenate
Coupling state: LEAK, OXPHOS, ET Pathway: N, S, NS HRR: Oxygraph-2k