Abstract 15838: Vascular Endothelial Growth Factor Myocardial Cell Anti-apoptotic Events Requires S100A6 Signaling
Introduction: Coronary artery bypass graft (CABG)-related cardiomyocyte apoptosis can result from overproduction of reactive oxygen species (ROS) following restoration of coronary blood flow. A number of endothelial markers including vascular endothelial growth factor (VEGF) may be released post CABG that may modulate the cardiomyocyte apoptotic response.
Hypothesis: We aimed to determine a possible role for VEGF in CABG-induced cardiomyocyte apoptosis.
Methods: During CABG surgery with cardiopulmonary bypass (CPB), sequential biopsies were taken from the right atrial appendage (RAA) before CPB and after aortic cross clamp release. The apoptotic markers caspase 3 activity, BAX and BCL2 mRNA, along with VEGF, the VEGF receptors VEGFR2 (KDR) and VEGFR3 (FLT-1) mRNA and protein were assessed in the RAA.
Results: The patient group consisted of 15 women and 42 men with a mean ± S.E. age of 66.57±1.78 and 63.02±1.15 years respectively. CPB was associated with increased myocyte apoptosis as assessed by a 3.5 fold increase in the BAX/BCL2 mRNA ratio and a 15 per cent increase in caspase 3 activity in the RAA. VEGF and VEGFR3 mRNA and protein in the RAA and circulating (serum) VEGF were increased approximately 2-3 fold. There were negative correlations between RAA VEGF and BAX/BCL2 mRNAs (r=-0.279, p=0.032) and RAA VEGFR3 and BAX/BCL2 mRNAs (r=-0.494, p<0.001). Interestingly, there were positive correlations between RAA VEGF and the anti-apoptotic S100 calcium binding protein S100A6 (r=0.471, p<0.001) and RAA VEGFR3 and S100A6 (r=0.437, p<0.001).Mechanistically, treatment of cultured neonatal rat neonatal rat cardiomyocytes with VEGF (1 nM) increased S100A6 protein and mRNA 2-3 fold and inhibited the H2O2-induced increase in the BAX/BCL2 ratio, caspase-3 activity and TUNEL positive cardiomyocytes by 60-75 per cent. Whereas, in the presence of S100A6 siRNA, VEGF had no effect on H2O2-induced cardiomyocyte apoptosis.
Conclusions: VEGF ligand binding to VEGFR3 exerts cardiac protection via anti-apoptotic effects dependent on S100A6 signaling.
Author Disclosures: J. Tsoporis: None. I.K. Rizos: None. V. Salpeas: None. S. Izhar: None. G. Proteau: None. T.G. Parker: None.
- © 2016 by American Heart Association, Inc.