title: Protein kinase RNA-like endoplasmic reticulum kinase (PERK)/calcineurin signaling is a novel pathway regulating intracellular calcium accumulation which might be involved in ventricular arrhythmias in diabetic cardiomyopathy.
abstract: We previously found that endoplasmic reticulum (ER) stress was involved in ventricular arrhythmias in diabetic cardiomyopathy. The present study was aimed to investigate the possible mechanism. In the in vivo study, diabetes cardiomyopathy (DCM) was induced by streptozotocin (STZ) injection. Hemodynamic and plasma brain natriuretic peptide (BNP) detections were used to evaluate cardiac functions; ECG was used to assess the vulnerability to arrhythmias by recording ventricular arrhythmia events (VAEs). In the in vitro study, high-glucose incubation was employed to mimic the diabetic environment of myocytes. Immunofluorescent staining was used to investigate the nuclear factor of activated T cells (NFAT) nuclear translocation and (FK506-binding protein 12.6) FKBP12.6 disassociation. [(3)H]-ryanodine binding assay was implemented to assess the channel activity of ryanodine receptor. In both in vivo and in vitro studies, activity of calcineurin was determined by colorimetric method, and western blotting was used to detect protein expression levels. In the in vivo study, we found that inhibition of both of ER stress and PERK activation decreased the VAEs in DCM rats, accompanied by reduced activity of calcineurin in myocardial tissue. In the in vitro study, in high-glucose incubated myocytes, the depletion of PERK reduced activity of calcineurin, decreased NFAT translocation and FKBP12.6 disassociation from ryanodine receptor 2 (RyR2). Furthermore, PERK deletion also reduced RyR2 channel activity and consequently impaired intracellular calcium accumulation. We concluded that PERK/calcineurin-pathway was involved in intracellular calcium regulation in myocytes in diabetic heart, which might be the mechanism inducing arrhythmias in DCM.
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, China.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, First Affiliated Hospital of Xi'an Jiaotong University, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Cai
authors.affiliation: School of Medicine, Xi'an Jiaotong University, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology and Toxicology, GA Regents University, USA.
authors.forename: Haroldo
authors.initials: H
authors.lastname: Toque
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhao
authors.affiliation: School of Public Health & Tropical Medicine, Tulane University, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: Qiu
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, China.
authors.forename: Gongchang
authors.initials: G
authors.lastname: Guan
authors.affiliation: Department of Forensic Science, Xi'an Jiaotong University School of Medicine, China. Electronic address: psydyh@mail.xjtu.edu.cn.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Dang
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, China. Electronic address: junkuiwang@yeah.net.
authors.forename: Junkui
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D058065:Diabetic Cardiomyopathies / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D019703:Calcineurin; D002118:Calcium; D050778:NFATC Transcription Factors; D020097:Natriuretic Peptide, Brain; D019837:Ryanodine Receptor Calcium Release Channel; D022021:Tacrolimus Binding Proteins; D019892:eIF-2 Kinase; C403484:tacrolimus binding protein 1B
keywords: Arrhythmias; Diabetic cardiomyopathy; Endoplasmic reticulum stress; PERK