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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.
Highlights
Development of the heart is guided by secreted morphogens including members of the transforming growth factor (TGF)-b superfamily.[1]
Activins and growth differentiation factors (GDF) bind to activin receptor IIA and B (ACVR2A and ACVR2B),[2,3] which in turn activate type I receptors such as activin receptor-like kinases (ALK) ALK4 and ALK5, activating downstream molecule SMAD2/3.4,5 SMADSs regulate a number of myogenic genes, such as myoD, myogenin, and Myf[5], that are involved in cellular hypertrophy, proliferation, or differentiation.[6]
Systemic Blockade of ACVR2B Ligands Reduces Ischemic Injury and Restores Cardiac Function in an Experimental Model of Ischemia Reperfusion To study the contribution of ACVR2B signaling to ischemic myocardial injury, we treated mice with a soluble decoy receptor of ACVR2B 24 h before ischemia (“ACVR2B-Fc pretreatment”) to block the function of ACVR2B ligands and subjected the mice to transient IR by ligation of left anterior descending coronary artery (LAD). 30 min of ischemia followed by 6 h or 24 h of reperfusion resulted in left ventricular (LV) cell death and deteriorated cardiac function 24 h after IR
Summary
Development of the heart is guided by secreted morphogens including members of the transforming growth factor (TGF)-b superfamily.[1] In addition to their regulatory function in organogenesis, the TGF-b family of growth factors, including activins, bone morphogenetic proteins (BMPs), and growth differentiation factors (GDF), are known to regulate cardiac physiology and pathophysiology in the adult heart. These factors signal through type I and type II receptors, both of which are transmembrane serine and threonine kinases. Noncanonical ACVR2B pathways have been shown to regulate MAP kinases.[5]
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