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

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.

ACVR2B antagonism as a countermeasure to multi‐organ perturbations in metastatic colorectal cancer cachexia

“…In support of this observation, others have recently demonstrated that the myostatin/ACVR2B signalling is up-regulated in the heart of patients with heart failure 75 and that targeting ACVR2B can improve cardiac function in models of ageing, ischaemia, and myocardial infarction, thereby implicating activin signalling as a negative input on cardiac function. [76][77][78] To our knowledge, ours is the first report providing evidence that ACVR2B could represent a potent therapeutic target to preserve cardiac function in the occurrence of metastatic CRC. Interestingly, cardiac function is preserved despite no effects in terms of whole-heart size, LV mass, nor major impact on regulators of muscle growth, thereby suggesting that signalling through ACVR2B is not critical in regulating heart size in metastatic CRC.…”

Muscle NAD+ depletion and Serpina3n as molecular determinants of murine cancer cachexia—the effects of blocking myostatin and activins

“…Previously, blocking ACVR ligands has either had no effect [ 15 ] or even diminished mitochondrial oxidative capacity [ 14 , 37 , 38 ], and decreased OXPHOS-related protein expression in muscle [ 39 ] while inducing fast and glycolytic transformation [ 40 ]. However, blocking ACVR ligands has also resulted in positive outcomes in various disease, injury, and ageing models [ [4] , [5] , [6] , 15 , [40] , [41] , [42] ]. Our results imply that blocking ACVR ligands can have context-dependent effects on muscle oxidative metabolism.…”

Vezf1 regulates cardiac structure and contractile function

“…Mouse ventricular cardiomyocytes, cardiac endothelial cells and fibroblasts were isolated from 8-week old c57/BL6 mice as described previously [22]. Adult rat ventricular cardiomyocytes (ARVMs) were isolated from 8À12 weeks old male SD rats by retrograde perfusion and enzymatic digestion using collagenase type 2 (Worthington) as previously described [23]. After 2 h incubation, non-attached cells were gently removed and cells were transfected with desired siRNAs.…”