The Connexin 43 Regulator Rotigaptide Reduces Cytokine-Induced Cell Death in Human Islets
Background: Intercellular communication mediated by cationic fluxes through the Connexin family of gap junctions regulates glucose-stimulated insulin secretion and beta cell defense against inflammatory stress. Rotigaptide (RG, ZP123) is a peptide analog that increases intercellular conductance in c...
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MDPI AG
2020-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/12/4311 |
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| author | Seyed Mojtaba Ghiasi Jakob Bondo Hansen Dan Ploug Christensen Björn Tyrberg Thomas Mandrup-Poulsen |
| author_facet | Seyed Mojtaba Ghiasi Jakob Bondo Hansen Dan Ploug Christensen Björn Tyrberg Thomas Mandrup-Poulsen |
| author_sort | Seyed Mojtaba Ghiasi |
| collection | DOAJ |
| description | Background: Intercellular communication mediated by cationic fluxes through the Connexin family of gap junctions regulates glucose-stimulated insulin secretion and beta cell defense against inflammatory stress. Rotigaptide (RG, ZP123) is a peptide analog that increases intercellular conductance in cardiac muscle cells by the prevention of dephosphorylation and thereby uncoupling of Connexin-43 (Cx43), possibly via action on unidentified protein phosphatases. For this reason, it is being studied in human arrhythmias. It is unknown if RG protects islet cell function and viability against inflammatory or metabolic stress, a question of considerable translational interest for the treatment of diabetes. Methods: Apoptosis was measured in human islets shown to express Cx43, treated with RG or the control peptide ZP119 and exposed to glucolipotoxicity or IL-1β + IFNɣ. INS-1 cells shown to lack Cx43 were used to examine if RG protected human islet cells via Cx43 coupling. To study the mechanisms of action of Cx43-independent effects of RG, NO, IkBα degradation, mitochondrial activity, ROS, and insulin mRNA levels were determined. Results: RG reduced cytokine-induced apoptosis ~40% in human islets. In Cx43-deficient INS-1 cells, this protective effect was markedly blunted as expected, but unexpectedly, RG still modestly reduced apoptosis, and improved mitochondrial function, insulin-2 gene levels, and accumulated insulin release. RG reduced NO production in Cx43-deficient INS-1 cells associated with reduced iNOS expression, suggesting that RG blunts cytokine-induced NF-κB signaling in insulin-producing cells in a Cx43-independent manner. Conclusion: RG reduces cytokine-induced cell death in human islets. The protective action in Cx43-deficient INS-1 cells suggests a novel inhibitory mechanism of action of RG on NF-κB signaling. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T19:07:02Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5c165ff5cd914301a34443892d7c8b472023-11-20T04:04:56ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-06-012112431110.3390/ijms21124311The Connexin 43 Regulator Rotigaptide Reduces Cytokine-Induced Cell Death in Human IsletsSeyed Mojtaba Ghiasi0Jakob Bondo Hansen1Dan Ploug Christensen2Björn Tyrberg3Thomas Mandrup-Poulsen4Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London W12 0NN, UKNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen N, DenmarkDepartment of Biology, University of Copenhagen, 2200 Copenhagen N, DenmarkDepartment of Physiology, Sahlgrenska Academy, Gothenburg University, 40530 Gothenburg, SwedenDepartment of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen N, DenmarkBackground: Intercellular communication mediated by cationic fluxes through the Connexin family of gap junctions regulates glucose-stimulated insulin secretion and beta cell defense against inflammatory stress. Rotigaptide (RG, ZP123) is a peptide analog that increases intercellular conductance in cardiac muscle cells by the prevention of dephosphorylation and thereby uncoupling of Connexin-43 (Cx43), possibly via action on unidentified protein phosphatases. For this reason, it is being studied in human arrhythmias. It is unknown if RG protects islet cell function and viability against inflammatory or metabolic stress, a question of considerable translational interest for the treatment of diabetes. Methods: Apoptosis was measured in human islets shown to express Cx43, treated with RG or the control peptide ZP119 and exposed to glucolipotoxicity or IL-1β + IFNɣ. INS-1 cells shown to lack Cx43 were used to examine if RG protected human islet cells via Cx43 coupling. To study the mechanisms of action of Cx43-independent effects of RG, NO, IkBα degradation, mitochondrial activity, ROS, and insulin mRNA levels were determined. Results: RG reduced cytokine-induced apoptosis ~40% in human islets. In Cx43-deficient INS-1 cells, this protective effect was markedly blunted as expected, but unexpectedly, RG still modestly reduced apoptosis, and improved mitochondrial function, insulin-2 gene levels, and accumulated insulin release. RG reduced NO production in Cx43-deficient INS-1 cells associated with reduced iNOS expression, suggesting that RG blunts cytokine-induced NF-κB signaling in insulin-producing cells in a Cx43-independent manner. Conclusion: RG reduces cytokine-induced cell death in human islets. The protective action in Cx43-deficient INS-1 cells suggests a novel inhibitory mechanism of action of RG on NF-κB signaling.https://www.mdpi.com/1422-0067/21/12/4311beta cellinflammationinsulinNF-κBgap junctions |
| spellingShingle | Seyed Mojtaba Ghiasi Jakob Bondo Hansen Dan Ploug Christensen Björn Tyrberg Thomas Mandrup-Poulsen The Connexin 43 Regulator Rotigaptide Reduces Cytokine-Induced Cell Death in Human Islets International Journal of Molecular Sciences beta cell inflammation insulin NF-κB gap junctions |
| title | The Connexin 43 Regulator Rotigaptide Reduces Cytokine-Induced Cell Death in Human Islets |
| title_full | The Connexin 43 Regulator Rotigaptide Reduces Cytokine-Induced Cell Death in Human Islets |
| title_fullStr | The Connexin 43 Regulator Rotigaptide Reduces Cytokine-Induced Cell Death in Human Islets |
| title_full_unstemmed | The Connexin 43 Regulator Rotigaptide Reduces Cytokine-Induced Cell Death in Human Islets |
| title_short | The Connexin 43 Regulator Rotigaptide Reduces Cytokine-Induced Cell Death in Human Islets |
| title_sort | connexin 43 regulator rotigaptide reduces cytokine induced cell death in human islets |
| topic | beta cell inflammation insulin NF-κB gap junctions |
| url | https://www.mdpi.com/1422-0067/21/12/4311 |
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