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; Toque, Haroldo A.; Zhao, Na; Qin, Chuan; Guan, Gongchang; Dang, Yonghui; Wang, Junkui

doi:10.1016/j.cellsig.2014.08.015

Cited by 58 publications

(50 citation statements)

References 45 publications

(45 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PERK dimerizes with Grp78 in resting cells, and oligomerizes and thus is activated in ER-stressed cells. Activated PERK phosphorylates the alpha subunit of eukaryotic translation- initiation factor 2 (EIF2) and causes its inactivation and thus a rapid reduction of translational initiation and repression of global protein synthesis, leading to growth arrest [41]. In HG-treated podocytes, the phospho-PERKThr982 was remarkably upregulated.…”

Section: Discussionmentioning

confidence: 99%

High Glucose-Induced Podocyte Injury Involves Activation of Mammalian Target of Rapamycin (mTOR)-Induced Endoplasmic Reticulum (ER) Stress

Lei

Zhao

Zhang

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: The mechanisms by which high glucose (HG) results in podocyte damage remains unclear. We investigated the potential role of endoplasmic reticulum (ER) stress and mTOR signaling in HG injured podocyte. Methods: In cultured mouse podocytes, cellular apoptosis was assessed using FITC-Annexin V and propidium iodide staining followed by flow cytometry analysis. Apoptosis-related proteins as well as the ER stress and the mTOR signals were evaluated using immunoblot assay. Results: Compared to normal glucose (NG) and osmotic mannitol (MN) control, the percentage of apoptotic cells was increased significantly in HG-treated podocytes. The levels of CHOP, Grp78, phospho-PERKThr982, and caspase-12 were increased significantly following HG treatment. The downstream effects of ER stress were obtained in HG-treated podocytes, showing upregulation of Bax, Bak and cytochrome c, and downregulation of Bcl-2. HG-induced increase of cytochrome c, Bax and active caspase-3 was prevented by both ER inhibitor sodium 4-phenylbultyrate (PBA) and CHOP siRNA (siCHOP). PBA and CHOP knockdown remarkably decreased HG-induced apoptosis. In addition, the levels of phospho-mTORSer2448 and phospho- p70S6kThr389 as well as phospho-AMPKα (a sensor of energy consumption) were increased significantly in HG-treated cells. Moreover, the Erk inhibitor U0126 prevented HG-induced mTOR activation. Increased phospho-AMPKα, CHOP and Grp78 as well as cellular apoptosis were prevented by mTOR inhibitor rapamycin in HG-treated podocytes. Conclusion: Our data demonstrate that the activated mTOR by Erk1/2 results in energy consumption, which in turn leads to ER stress signaling and thus induces apoptosis in HG-treated podocytes.

show abstract

Section: Discussionmentioning

confidence: 99%

High Glucose-Induced Podocyte Injury Involves Activation of Mammalian Target of Rapamycin (mTOR)-Induced Endoplasmic Reticulum (ER) Stress

Lei

Zhao

Zhang

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…Recently, PERK has been demonstrated to play a cardioprotective role in heart failure. The inducible cardiac‐specific PERK knockout mice showed enhanced cardiac dysfunction, fibrosis and apoptosis compared with wild‐type mice after TAC (Liu et al, ,b). In PERK knockout heart, the expression of CHOP was increased in response to TAC, which indicates that CHOP‐induced apoptosis may contribute to heart failure.…”

Section: Er Stress In Cardiac Hypertrophy and Heart Failurementioning

confidence: 99%

“…In rats with diabetic cardiomyopathy, inhibition of PERK in association with reduced activity of calcineurin decreased arrhythmias (Liu et al, ,b). An in vitro study also demonstrated that PERK activation was required in the activation of calcineurin and the dissociation of the FK506 binding protein 1B, 12.6 kDa from the ryanodine receptor 2 (RyR2) (Liu et al, ,b). Thus, PERK activated calcineurin to facilitate degradation of FKBP‐RyR2 complex leading to intracellular calcium accumulation, which might be a mechanism inducing arrhythmias.…”

Section: Er Stress In Arrhythmiasmentioning

confidence: 99%

Endoplasmic reticulum stress in the heart: insights into mechanisms and drug targets

Wang

Binder

Fang³

et al. 2017

British J Pharmacology

144

View full text Add to dashboard Cite

show abstract

“…The protocols were carried out in accordance with our previous investigation [10]. Cultured primary myocytes were xed by 4% paraformaldehyde for 15 min and permeabilized by 0.2% Triton on a cover glass.…”

Section: Immuno Uorescent Stainingmentioning

confidence: 99%

“…By direct contacting, PERK activates calcineurin (CaN) which further facilitates ER calcium releasing via promoting the disassociation of FK506-binding protein 12.6 (FKBP12.6) from RyR2 [9]. Our previous investigation indicated that ER stress PERK signaling was activated in diabetic hearts, inducing ventricular arrhythmias through the PERK/CaN signaling [10].…”

mentioning

confidence: 99%

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

Liu¹,

Zhang²,

Pan³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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). [3H]-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.

show abstract

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

Cited by 58 publications

References 45 publications

High Glucose-Induced Podocyte Injury Involves Activation of Mammalian Target of Rapamycin (mTOR)-Induced Endoplasmic Reticulum (ER) Stress

High Glucose-Induced Podocyte Injury Involves Activation of Mammalian Target of Rapamycin (mTOR)-Induced Endoplasmic Reticulum (ER) Stress

Endoplasmic reticulum stress in the heart: insights into mechanisms and drug targets

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

Contact Info

Product

Resources

About