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

Zhongwei Liu, Hui Cai, Haitao Zhu, Haroldo Alfredo Flores Toque, Na Zhao, Chuan Qiu, Gongchang Guan, Yonghui Dang, Junkui Wang

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2591-2600
Number of pages10
JournalCellular Signalling
Volume26
Issue number12
DOIs
StatePublished - Dec 1 2014

Fingerprint

Diabetic Cardiomyopathies
Calcineurin
Endoplasmic Reticulum
Protein Kinases
Cardiac Arrhythmias
Ryanodine Receptor Calcium Release Channel
RNA
Calcium
Cardiomyopathies
Muscle Cells
NFATC Transcription Factors
Endoplasmic Reticulum Stress
Tacrolimus Binding Proteins
Glucose
Ryanodine
Brain Natriuretic Peptide
Streptozocin
Electrocardiography
Hemodynamics
Western Blotting

Keywords

  • Arrhythmias
  • Diabetic cardiomyopathy
  • Endoplasmic reticulum stress
  • PERK

ASJC Scopus subject areas

  • Cell Biology

Cite this

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. / Liu, Zhongwei; Cai, Hui; Zhu, Haitao; Flores Toque, Haroldo Alfredo; Zhao, Na; Qiu, Chuan; Guan, Gongchang; Dang, Yonghui; Wang, Junkui.

In: Cellular Signalling, Vol. 26, No. 12, 01.12.2014, p. 2591-2600.

Research output: Contribution to journalArticle

@article{80133bf3d6974069b524e8fe31efca66,
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.",
keywords = "Arrhythmias, Diabetic cardiomyopathy, Endoplasmic reticulum stress, PERK",
author = "Zhongwei Liu and Hui Cai and Haitao Zhu and {Flores Toque}, {Haroldo Alfredo} and Na Zhao and Chuan Qiu and Gongchang Guan and Yonghui Dang and Junkui Wang",
year = "2014",
month = "12",
day = "1",
doi = "10.1016/j.cellsig.2014.08.015",
language = "English (US)",
volume = "26",
pages = "2591--2600",
journal = "Cellular Signalling",
issn = "0898-6568",
publisher = "Elsevier Inc.",
number = "12",

}

TY - JOUR

T1 - 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

AU - Liu, Zhongwei

AU - Cai, Hui

AU - Zhu, Haitao

AU - Flores Toque, Haroldo Alfredo

AU - Zhao, Na

AU - Qiu, Chuan

AU - Guan, Gongchang

AU - Dang, Yonghui

AU - Wang, Junkui

PY - 2014/12/1

Y1 - 2014/12/1

N2 - 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.

AB - 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.

KW - Arrhythmias

KW - Diabetic cardiomyopathy

KW - Endoplasmic reticulum stress

KW - PERK

UR - http://www.scopus.com/inward/record.url?scp=84907717563&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907717563&partnerID=8YFLogxK

U2 - 10.1016/j.cellsig.2014.08.015

DO - 10.1016/j.cellsig.2014.08.015

M3 - Article

VL - 26

SP - 2591

EP - 2600

JO - Cellular Signalling

JF - Cellular Signalling

SN - 0898-6568

IS - 12

ER -