Vagus nerve stimulation optimized cardiomyocyte phenotype, sarcomere organization and energy metabolism in infarcted heart through FoxO3A-VEGF signaling

Abstract

Vagus nerve stimulation (VNS) restores autonomic balance, suppresses inflammation action and minimizes cardiomyocyte injury. However, little knowledge is known about the VNS’ role in cardiomyocyte phenotype, sarcomere organization, and energy metabolism of infarcted hearts. VNS in vivo and acetylcholine (ACh) in vitro optimized the levels of α/β-MHC and α-Actinin positive sarcomere organization in cardiomyocytes while reducing F-actin assembly of cardiomyocytes. Consistently, ACh improved glucose uptake while decreasing lipid deposition in myocytes, correlating both with the increase of Glut4 and CPT1α and the decrease of PDK4 in infarcted hearts in vivo and myocytes in vitro, attributing to improvement in both glycolysis by VEGF-A and lipid uptake by VEGF-B in response to Ach. This led to increased ATP levels accompanied by the repaired mitochondrial function and the decreased oxygen consumption. Functionally, VNS improved the left ventricular performance. In contrast, ACh-m/nAChR inhibitor or knockdown of VEGF-A/B by shRNA powerfully abrogated these effects mediated by VNS. On mechanism, ACh decreased the levels of nuclear translocation of FoxO3A in myocytes due to phosphorylation of FoxO3A by activating AKT. FoxO3A overexpression or knockdown could reverse the specific effects of ACh on the expression of VEGF-A/B, α/β-MHC, Glut4, and CPT1α, sarcomere organization, glucose uptake and ATP production. Taken together, VNS optimized cardiomyocytes sarcomere organization and energy metabolism to improve heart function of the infarcted heart during the process of delaying and/or blocking the switch from compensated hypertrophy to decompensated heart failure, which were associated with activation of both P13K/AKT-FoxO3A-VEGF-A/B signaling cascade.

C‐C motif chemokine ligand 5 confines liver regeneration by down‐regulating reparative macrophage‐derived hepatocyte growth factor in a forkhead box O 3a–dependent manner

“…[ 39 ] In addition, the enhanced expression of FoxO3a markedly abolishes the release of VEGF mediated by protein kinase B (AKT) in cardiomyocytes. [ 46 ] These reports on FoxO3a indicate that it is closely related to increased synthesis of proinflammatory mediators and decreased production of reparative cytokines. In this study, we found that the alternation of FoxO3a phosphorylation is responsible for CCL5‐induced HGF regulation after PHx.…”

Continuous exposure to isoprenaline reduced myotube size by delaying myoblast differentiation and fusion through the NFAT-MEF2C signaling pathway

“…Constructions of NFATc1/c2/c4 overexpression adenoviral vectors were prepared as previously described 17 . The gene accession numbers of overexpressing NFATc1/c2/c4 are NM_172390, NM_173091, and NM_004554, respectively.…”

“…The gene accession numbers of overexpressing NFATc1/c2/c4 are NM_172390, NM_173091, and NM_004554, respectively. Constructions of NFATc3/c4 short hairpin RNA (shRNA) adenoviral vectors were prepared as previously described 17 . These overexpression adenoviral vectors containing Ad-NFATc1, Ad-NFATc2, Ad-shNFATc3 and Ad-shNFATc4 were obtained from Vigenebio.…”

“…One is a short myotube with 3 ~ 5 myoblast fusions; the other is a long myotube with more than 5 myoblast fusions. Morphology was assessed by myotube length, area (two types, less than 200 μm and more than 200 μm) and number of myotubes with myoblast fusion (3 ~ 5 nuclei or more than 5 nuclei) under high-power magnification 17 , 19 . Images were evaluated by two people who did not know the results using ImageJ (Java) software (National Institutes of Health, USA).…”

Study of variants associated with ventricular septal defects (VSDs) highlights the unique genetic structure of the Pakistani population

“…A polymorphism rs7240256 (NG_029226.1:g.23449 T > C) in this gene has been reported as a risk factor of VSD. Vascular endothelial growth factor ( VEGF ) plays a key role in morphogenesis of the vascular system and differentiation of endothelial cells [ 11 ]. The human VEGF gene is located on chromosome 6p21.1.…”