title: The ER stress-mediated mitochondrial apoptotic pathway and MAPKs modulate tachypacing-induced apoptosis in HL-1 atrial myocytes.
abstract: OBJECTIVE
  Cell apoptosis is a contributing factor in the initiation, progression and relapse of atrial fibrillation (AF), a life-threatening illness accompanied with stroke and heart failure. However, the regulatory cascade of apoptosis is intricate and remains unidentified, especially in the setting of AF. The aim of this study was to explore the roles of endoplasmic reticulum (ER) stress, mitochondrial apoptotic pathway (MAP), mitogen-activated protein kinases (MAPKs), and their cross-talking in tachypacing-induced apoptosis.
  
  
  RESULTS
  HL-1 cells were cultured in the presence of tachypacing for 24 h to simulate atrial tachycardia remodeling. Results showed that tachypacing reduced cell viability measured by the cell counting kit-8, dissipated mitochondrial membrane potential detected by JC-1 staining and resulted in approximately 50% apoptosis examined by Hoechst staining and annexin V/propidium iodide staining. In addition, the proteins involved in ER stress, MAP and MAPKs were universally up-regulated or activated via phosphorylation, as confirmed by western blotting; and reversely silencing of ER stress, caspase-3 (the ultimate executor of MAP) and MAPKs with specific inhibitors prior to pacing partially alleviated apoptosis. An inhibitor of ER stress was applied to further investigate the responses of mitochondria and MAPKs to ER stress, and results indicated that suppression of ER stress comprehensively but incompletely attenuated the activation of MAP and MAPKs aroused by tachypacing, with the exception of ERK1/2, one branch of MAPKs.
  
  
  CONCLUSIONS
  Our study suggested tachypacing-induced apoptosis is regulated by ER stress-mediated MAP and MAPKs. Thus, the above three components are all promising anti-apoptotic targets in AF patients and ER stress appears to play a dominant role due to its comprehensive effects.
authors.affiliation: Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Shi
authors.affiliation: Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Xiangwei
authors.initials: X
authors.lastname: Ding
authors.affiliation: Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Xu
authors.affiliation: Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Dao W
authors.initials: DW
authors.lastname: Wang
authors.affiliation: Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Minglong
authors.initials: M
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis; D064752:Atrial Remodeling; D045744:Cell Line, Tumor; D002470:Cell Survival; D059865:Endoplasmic Reticulum Stress; D006325:Heart Atria / Q000473:pathology*; D020935:MAP Kinase Signaling System; D051379:Mice; D008928:Mitochondria / Q000473:pathology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000473:pathology*; D013610:Tachycardia / Q000473:pathology* / Q000503:physiopathology; D013997:Time Factors
chemical_list: D020928:Mitogen-Activated Protein Kinases