Hyper-Activation of Endoplasmic Reticulum Stress PERK/Calcineurin/RyR2 Signaling Pathway is Involved in AGEs-Exacerbated Post- Myocardial Infarction Ventricular Arrhythmias

Background: The current study was aimed to investigate the mechanisms of advanced glycation end products (AGEs) in exacerbating post- myocardial infarction (MI) ventricular arrhythmias (VAs). Methods: Correlation between premature ventricular contractions (PVCs) and serum AGEs concentrations was analyzed in a cohort consisted of 101 STEMI patients with culprit vessel of left anterior descending artery (LAD). Established MI rat model were treated with AGEs and/or anti- receptor for AGE (RAGE) antibody. Electrocardiography was used to record VAs. Myocytes were isolated from adjacent area around infracted region. Immunofluorescent stains were used to evaluate association between FKBP12.6 (FK506-bindingprotein 12.6) and ryanodine receptor 2 (RyR2). Calcium sparks were evaluated by confocal microscope. Protein expression and phosphorylation were assessed by Western blotting. A colorimetric method was used to determine the enzymatic activity of calcineurin (CaN). [ 3 H]-ryanodine binding assay was carried out to detect the RyR2 channel activity. Results: In the cohort study, significantly increased amount of (PVCs) were found in STEMI patients with diabetes (P<0.05). Serum AGEs concentration was significantly positively correlated with PVCs amount in STEMI patients (r=0.416, P<0.001). Multivariate analysis showed serum AGEs concentration was independently and positively related to frequent PVCs (adjusted hazard ratio, 1.86; 95% CI, 1.09-3.18, P=0.022). In the animal study, increased glucose regulated protein 78 (GRP78) expression, protein kinase RNA-like ER kinase (PERK) phosphorylation, CaN enzymatic activity, FKBP12.6-RyR2 disassociation, RyR2 channel opening and endoplasmic reticulum (ER) calcium releasing were found in MI animals exposed to AGEs, which were attenuated by anti-RAGE antibody treatment. This RAGE blocking also significantly lowered the VAs amount in MI animals exposed to AGEs. Conclusions: Hyper-activation of ER stress- mediated PERK/CaN/RyR2 signaling participated in AGEs- exacerbated post-MI VAs.