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      Ibutilide treatment protects against ER stress induced apoptosis by regulating calumenin expression in tunicamycin treated cardiomyocytes

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          Abstract

          Background

          Ibutilide, a class III antiarrhythmic agent has been shown to be cardioprotective in treating atrial fibrillation, promoting cardioconversion and recently this agent has been shown to protect against ER stress induced apoptosis in cardiomyocytes. In this study we begin to identify the mechanism by which ibutilide exerts its cardioprotection in tunicamycin treated cardiomyocytes. We examined ER stress markers including calumenin; a calcium binding ER chaperone protein that has recently been linked to ER stress in cardiomyocytes, in our treated cells.

          Methods

          To assess the effect of ibutilide we used the well characterized in vitro model of ER stress induced apoptosis in rat neonatal cardiomyocytes (RNC). RNC were treated with tunicamycin and the degree of ER stress was assessed by quantifying mRNA and protein levels of GRP78, GRP94 and calumenin, and examined the extent of apoptosis by assessing the protein levels of caspase-3/9/12, CHOP, ATF6, p-PERK, spliced XBP-1, the ratio of Bax/Bcl-2 and the percentage of deoxynucleotidyl-transferase- mediated dUTP nick end labeling (TUNEL) positive cells.

          Results

          We demonstrate ibutilide attenuated the up-regulation of ER stress markers GRP78 and GRP94 and rescued the decline in calumenin mRNA and protein levels in tunicamycin treated cardiomyocytes. The up-regulation of apoptotic markers caspase-3, CHOP, ATF6, p-PERK, spliced XBP-1, the ratio of Bax/Bcl-2 and the percentage of TUNEL positive cells were also attenuated after ibutilide treatment while the protein levels of Caspase-9 and Caspase-12 were unaffected.

          Conclusions

          This study suggests another cardioprotective effect of the antiarrhythmic agent ibutilide whereby pretreatment leads to the attenuation of ER stress induced apoptosis by regulating calumenin expression. This study provides further evidence for the role of calumenin in the cardiomyocyte ER stress response.

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          Most cited references20

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          Protein quality control in the early secretory pathway.

          Tiziana Anelli, Roberto Sitia (2008)
          Eukaryotic cells are able to discriminate between native and non-native polypeptides, selectively transporting the former to their final destinations. Secretory proteins are scrutinized at the endoplasmic reticulum (ER)-Golgi interface. Recent findings reveal novel features of the underlying molecular mechanisms, with several chaperone networks cooperating in assisting the maturation of complex proteins and being selectively induced to match changing synthetic demands. 'Public' and 'private' chaperones, some of which enriched in specializes subregions, operate for most or selected substrates, respectively. Moreover, sequential checkpoints are distributed along the early secretory pathway, allowing efficiency and fidelity in protein secretion.
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            Biology of endoplasmic reticulum stress in the heart.

            Jody Groenendyk, Pradeep Kumar Sreenivasaiah, Do Han Kim … (2010)
            The endoplasmic reticulum (ER) is a multifunctional intracellular organelle supporting many processes required by virtually every mammalian cell, including cardiomyocytes. It performs diverse functions, including protein synthesis, translocation across the membrane, integration into the membrane, folding, posttranslational modification including N-linked glycosylation, and synthesis of phospholipids and steroids on the cytoplasmic side of the ER membrane, and regulation of Ca(2+) homeostasis. Perturbation of ER-associated functions results in ER stress via the activation of complex cytoplasmic and nuclear signaling pathways, collectively termed the unfolded protein response (UPR) (also known as misfolded protein response), leading to upregulation of expression of ER resident chaperones, inhibition of protein synthesis and activation of protein degradation. The UPR has been associated with numerous human pathologies, and it may play an important role in the pathophysiology of the heart. ER stress responses, ER Ca(2+) buffering, and protein and lipid turnover impact many cardiac functions, including energy metabolism, cardiogenesis, ischemic/reperfusion, cardiomyopathies, and heart failure. ER proteins and ER stress-associated pathways may play a role in the development of novel UPR-targeted therapies for cardiovascular diseases.
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              Chronic rapid atrial pacing. Structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation.

              Helen Jones, Carlos Morillo, C Guiraudon … (1995)
              Despite the clinical importance of atrial fibrillation (AF), the development of chronic nonvalvular AF models has been difficult. Animal models of sustained AF have been developed primarily in the short-term setting. Recently, models of chronic ventricular myopathy and fibrillation have been developed after several weeks of continuous rapid ventricular pacing. We hypothesized that chronic rapid atrial pacing would lead to atrial myopathy, yielding a reproducible model of sustained AF. Twenty-two halothane-anesthetized mongrel dogs underwent insertion of a transvenous lead at the right atrial appendage that was continuously paced at 400 beats per minute for 6 weeks. Two-dimensional echocardiography was performed in 11 dogs to assess the effects of rapid atrial pacing on atrial size. Atrial vulnerability was defined as the ability to induce sustained repetitive atrial responses during programmed electrical stimulation and was assessed by extrastimulus and burst-pacing techniques. Effective refractory period (ERP) was measured at two endocardial sites in the right atrium. Sustained AF was defined as AF > or = 15 minutes. In animals with sustained AF, 10 quadripolar epicardial electrodes were surgically attached to the right and left atria. The local atrial fibrillatory cycle length (AFCL) was measured in a 20-second window, and the mean AFCL was measured at each site. Marked biatrial enlargement was documented; after 6 weeks of continuous rapid atrial pacing, the left atrium was 7.8 +/- 1 cm2 at baseline versus 11.3 +/- 1 cm2 after pacing, and the right atrium was 4.3 +/- 0.7 cm2 at baseline versus 7.2 +/- 1.3 cm2 after pacing. An increase in atrial area of at least 40% was necessary to induce sustained AF and was strongly correlated with the inducibility of AF (r = .87). Electron microscopy of atrial tissue demonstrated structural changes that were characterized by an increase in mitochondrial size and number and by disruption of the sarcoplasmic reticulum. After 6 weeks of continuous rapid atrial pacing, sustained AF was induced in 18 dogs (82%) and nonsustained AF was induced in 2 dogs (9%). AF occurred spontaneously in 4 dogs (18%). Right atrial ERP, measured at cycle lengths of 400 and 300 milliseconds at baseline, was significantly shortened after pacing, from 150 +/- 8 to 127 +/- 10 milliseconds and from 147 +/- 11 to 123 +/- 12 milliseconds, respectively (P < .001). This finding was highly predictive of inducibility of AF (90%). Increased atrial area (40%) and ERP shortening were highly predictive for the induction of sustained AF (88%). Local epicardial ERP correlated well with local AFCL (R2 = .93). Mean AFCL was significantly shorter in the left atrium (81 +/- 8 milliseconds) compared with the right atrium 94 +/- 9 milliseconds (P < .05). An area in the posterior left atrium was consistently found to have a shorter AFCL (74 +/- 5 milliseconds). Cryoablation of this area was attempted in 11 dogs. In 9 dogs (82%; mean, 9.0 +/- 4.0; range, 5 to 14), AF was terminated and no longer induced after serial cryoablation. Sustained AF was readily inducible in most dogs (82%) after rapid atrial pacing. This model was consistently associated with biatrial myopathy and marked changes in atrial vulnerability. An area in the posterior left atrium was uniformly shown to have the shortest AFCL. The results of restoration of sinus rhythm and prevention of inducibility of AF after cryoablation of this area of the left atrium suggest that this area may be critical in the maintenance of AF in this model.
              Article 0 comments Cited 94 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Salvatore V Pizzo: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 11 April 2017
                Publication date Collection: 2017
                Volume: 12
                Issue: 4
                Electronic Location Identifier: e0173469
                Affiliations
                [1 ]Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, P.R. China
                [2 ]Inner Mongolia Provincial Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, Inner Mongolia, P.R. China
                [3 ]First Clinical Medical College of Inner Mongolia University for Nationalities, Tongliao, Inner Mongolia, P.R. China
                Duke University School of Medicine, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: MZ CXW.

                • Data curation: XXC.

                • Formal analysis: SQC.

                • Funding acquisition: MZ CXW YW.

                • Investigation: MZ.

                • Methodology: YW.

                • Project administration: MZ.

                • Resources: CXW.

                • Software: YLW.

                • Supervision: MZ.

                • Validation: XXC.

                • Visualization: LYX.

                • Writing – original draft: YW.

                • Writing – review & editing: YW.

                Article
                Publisher ID: PONE-D-16-22646
                DOI: 10.1371/journal.pone.0173469
                PMC ID: 5388464
                PubMed ID: 28399139
                SO-VID: 69339af1-4f90-4838-9877-2e7f05498d5d
                Copyright © © 2017 Wang et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 20 June 2016
                Date accepted : 22 February 2017
                Page count
                Figures: 7, Tables: 0, Pages: 15
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81360587
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100004763, Natural Science Foundation of Inner Mongolia;
                Award ID: 2016BS0806
                Award Recipient :
                Funded by: the Mongolian medicine systems biology science and technology innovation team plan of Inner Mongolia
                Award Recipient :
                The study was supported by a grant from the National Natural Science Foundation of China (No. 81360587), the Natural Science Foundation of Inner Mongolia (No. 2016BS0806) and the Mongolian Medicine Systems Biology Science and Technology Innovation Team Plan of Inner Mongolia.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cell Processes
                Subject: Cell Death
                Subject: Apoptosis
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Structures and Organelles
                Subject: Endoplasmic Reticulum
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cell Processes
                Subject: Secretory Pathway
                Subject: Endoplasmic Reticulum
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Chaperone Proteins
                Subject: Biology and Life Sciences
                Subject: Molecular Biology
                Subject: Molecular Biology Techniques
                Subject: Molecular Biology Assays and Analysis Techniques
                Subject: Gene Expression and Vector Techniques
                Subject: Protein Expression
                Subject: Research and Analysis Methods
                Subject: Molecular Biology Techniques
                Subject: Molecular Biology Assays and Analysis Techniques
                Subject: Gene Expression and Vector Techniques
                Subject: Protein Expression
                Subject: Biology and life sciences
                Subject: Genetics
                Subject: Gene expression
                Subject: Gene regulation
                Subject: Small interfering RNAs
                Subject: Biology and life sciences
                Subject: Biochemistry
                Subject: Nucleic acids
                Subject: RNA
                Subject: Non-coding RNA
                Subject: Small interfering RNAs
                Subject: Medicine and Health Sciences
                Subject: Cardiology
                Subject: Arrhythmia
                Subject: Atrial Fibrillation
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Gene Expression
                Subject: Biology and Life Sciences
                Subject: Molecular Biology
                Subject: Molecular Biology Techniques
                Subject: Transfection
                Subject: Research and Analysis Methods
                Subject: Molecular Biology Techniques
                Subject: Transfection
                Custom metadata
                Data Availability All relevant data are within the paper.

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