From Ca2+ dysregulation to heart failure: β-adrenoceptor activation by RKIP postpones molecular damages and subsequent cardiac dysfunction in mice carrying mutant PLNR9C by correction of aberrant Ca2+-handling
Impaired cardiomyocyte Ca2+ handling is a central hallmark of heart failure (HF), which causes contractile dysfunction and arrhythmias. However, the underlying molecular mechanisms and the precise contribution of defects in Ca2+-cycling regulation in the development of HF are still not completely re...
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Elsevier
2025-01-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661824005036 |
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| author | Theresa Brand Bettina Tanitha Baumgarten Sabrina Denzinger Yvonne Reinders Miriam Kleindl Constanze Schanbacher Florian Funk Nilgün Gedik Mahmood Jabbasseh Petra Kleinbongard Jan Dudek Julia Szendroedi Elen Tolstik Kai Schuh Martina Krüger Dobromir Dobrev Friederike Cuello Albert Sickmann Joachim P. Schmitt Kristina Lorenz |
| author_facet | Theresa Brand Bettina Tanitha Baumgarten Sabrina Denzinger Yvonne Reinders Miriam Kleindl Constanze Schanbacher Florian Funk Nilgün Gedik Mahmood Jabbasseh Petra Kleinbongard Jan Dudek Julia Szendroedi Elen Tolstik Kai Schuh Martina Krüger Dobromir Dobrev Friederike Cuello Albert Sickmann Joachim P. Schmitt Kristina Lorenz |
| author_sort | Theresa Brand |
| collection | DOAJ |
| description | Impaired cardiomyocyte Ca2+ handling is a central hallmark of heart failure (HF), which causes contractile dysfunction and arrhythmias. However, the underlying molecular mechanisms and the precise contribution of defects in Ca2+-cycling regulation in the development of HF are still not completely resolved. Here, we used transgenic mice that express a human mutation in the cardiomyocyte Ca2+-regulator phospholamban (PLNR9C-tg) causing severe HF due to a reduction in Ca2+ reuptake into the sarco(endo)plasmic reticulum (SR). PLNR9C-induced HF is a rapidly progressing condition characterized by prominent Ca2+ cycling and relaxation defects and premature death of mutation carriers. We found that endoplasmic reticulum (ER) and mitochondrial function are affected even before transition to overt HF. Early correction of aberrant Ca2+ cycling by cardiac expression of the Raf kinase inhibitor protein (RKIP), an endogenous activator of β-adrenoceptors (βAR), delayed the cellular alterations, functional failure and prolonged lifespan. Our study highlights the importance of early and persistent correction of Ca2 + dynamics, not only for excitation/contraction coupling, but also for the prevention of rather irreparable events on cardiac energetics and ER stress adaptations. The latter may even impede with later onset of Ca2+-related therapeutic interventions and should gain more focus for HF treatment. |
| format | Article |
| id | doaj-art-788069e5dff84173b9fac9cb8a4b03a8 |
| institution | DOAJ |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-788069e5dff84173b9fac9cb8a4b03a82025-08-20T02:44:24ZengElsevierPharmacological Research1096-11862025-01-0121110755810.1016/j.phrs.2024.107558From Ca2+ dysregulation to heart failure: β-adrenoceptor activation by RKIP postpones molecular damages and subsequent cardiac dysfunction in mice carrying mutant PLNR9C by correction of aberrant Ca2+-handlingTheresa Brand0Bettina Tanitha Baumgarten1Sabrina Denzinger2Yvonne Reinders3Miriam Kleindl4Constanze Schanbacher5Florian Funk6Nilgün Gedik7Mahmood Jabbasseh8Petra Kleinbongard9Jan Dudek10Julia Szendroedi11Elen Tolstik12Kai Schuh13Martina Krüger14Dobromir Dobrev15Friederike Cuello16Albert Sickmann17Joachim P. Schmitt18Kristina Lorenz19Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Str. 9, Würzburg 97078, GermanyLeibniz-Institut für Analytische Wissenschaften – ISAS - e.V., Bunsen-Kirchhoff-Str. 11, Dortmund 44139, GermanyInstitute of Pharmacology and Toxicology, University of Würzburg, Versbacher Str. 9, Würzburg 97078, GermanyLeibniz-Institut für Analytische Wissenschaften – ISAS - e.V., Bunsen-Kirchhoff-Str. 11, Dortmund 44139, GermanyLeibniz-Institut für Analytische Wissenschaften – ISAS - e.V., Bunsen-Kirchhoff-Str. 11, Dortmund 44139, GermanyInstitute of Pharmacology and Toxicology, University of Würzburg, Versbacher Str. 9, Würzburg 97078, GermanyInstitute of Pharmacology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, Düsseldorf 40225, Germany; Cardiovascular Research Institute Düsseldorf (CARID), Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, Düsseldorf 40225, GermanyInstitute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Hufelandstr. 55, Essen 45122, GermanyInstitute of Pharmacology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, Düsseldorf 40225, Germany; Cardiovascular Research Institute Düsseldorf (CARID), Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, Düsseldorf 40225, GermanyInstitute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Hufelandstr. 55, Essen 45122, GermanyComprehensive Heart Failure Center, University Hospital of Würzburg, Am Schwarzenberg 15, Würzburg 97078, GermanyDepartment of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, GermanyLeibniz-Institut für Analytische Wissenschaften – ISAS - e.V., Bunsen-Kirchhoff-Str. 11, Dortmund 44139, GermanyInstitute of Physiology, University of Würzburg, Würzburg, GermanyCardiovascular Research Institute Düsseldorf (CARID), Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, Düsseldorf 40225, Germany; Institute of Cardiovascular Physiology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, GermanyInstitute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Germany; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, United States; Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Quebec, CanadaDZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, University Medical Center Hamburg-Eppendorf, Germany; Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg, GermanyLeibniz-Institut für Analytische Wissenschaften – ISAS - e.V., Bunsen-Kirchhoff-Str. 11, Dortmund 44139, GermanyInstitute of Pharmacology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, Düsseldorf 40225, Germany; Cardiovascular Research Institute Düsseldorf (CARID), Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, Düsseldorf 40225, Germany; Correspondence to: Institute of Pharmacology, Düsseldorf University Hospital, Universitätsstraße 1, Düsseldorf 40225, Germany.Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Str. 9, Würzburg 97078, Germany; Leibniz-Institut für Analytische Wissenschaften – ISAS - e.V., Bunsen-Kirchhoff-Str. 11, Dortmund 44139, Germany; Comprehensive Heart Failure Center, University Hospital of Würzburg, Am Schwarzenberg 15, Würzburg 97078, Germany; Correspondence to: Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Str. 9, Würzburg 97078, Germany.Impaired cardiomyocyte Ca2+ handling is a central hallmark of heart failure (HF), which causes contractile dysfunction and arrhythmias. However, the underlying molecular mechanisms and the precise contribution of defects in Ca2+-cycling regulation in the development of HF are still not completely resolved. Here, we used transgenic mice that express a human mutation in the cardiomyocyte Ca2+-regulator phospholamban (PLNR9C-tg) causing severe HF due to a reduction in Ca2+ reuptake into the sarco(endo)plasmic reticulum (SR). PLNR9C-induced HF is a rapidly progressing condition characterized by prominent Ca2+ cycling and relaxation defects and premature death of mutation carriers. We found that endoplasmic reticulum (ER) and mitochondrial function are affected even before transition to overt HF. Early correction of aberrant Ca2+ cycling by cardiac expression of the Raf kinase inhibitor protein (RKIP), an endogenous activator of β-adrenoceptors (βAR), delayed the cellular alterations, functional failure and prolonged lifespan. Our study highlights the importance of early and persistent correction of Ca2 + dynamics, not only for excitation/contraction coupling, but also for the prevention of rather irreparable events on cardiac energetics and ER stress adaptations. The latter may even impede with later onset of Ca2+-related therapeutic interventions and should gain more focus for HF treatment.http://www.sciencedirect.com/science/article/pii/S1043661824005036Ca2+ dysregulationMitochondrial and ER defectsPLNR9CRKIPHeart failure |
| spellingShingle | Theresa Brand Bettina Tanitha Baumgarten Sabrina Denzinger Yvonne Reinders Miriam Kleindl Constanze Schanbacher Florian Funk Nilgün Gedik Mahmood Jabbasseh Petra Kleinbongard Jan Dudek Julia Szendroedi Elen Tolstik Kai Schuh Martina Krüger Dobromir Dobrev Friederike Cuello Albert Sickmann Joachim P. Schmitt Kristina Lorenz From Ca2+ dysregulation to heart failure: β-adrenoceptor activation by RKIP postpones molecular damages and subsequent cardiac dysfunction in mice carrying mutant PLNR9C by correction of aberrant Ca2+-handling Pharmacological Research Ca2+ dysregulation Mitochondrial and ER defects PLNR9C RKIP Heart failure |
| title | From Ca2+ dysregulation to heart failure: β-adrenoceptor activation by RKIP postpones molecular damages and subsequent cardiac dysfunction in mice carrying mutant PLNR9C by correction of aberrant Ca2+-handling |
| title_full | From Ca2+ dysregulation to heart failure: β-adrenoceptor activation by RKIP postpones molecular damages and subsequent cardiac dysfunction in mice carrying mutant PLNR9C by correction of aberrant Ca2+-handling |
| title_fullStr | From Ca2+ dysregulation to heart failure: β-adrenoceptor activation by RKIP postpones molecular damages and subsequent cardiac dysfunction in mice carrying mutant PLNR9C by correction of aberrant Ca2+-handling |
| title_full_unstemmed | From Ca2+ dysregulation to heart failure: β-adrenoceptor activation by RKIP postpones molecular damages and subsequent cardiac dysfunction in mice carrying mutant PLNR9C by correction of aberrant Ca2+-handling |
| title_short | From Ca2+ dysregulation to heart failure: β-adrenoceptor activation by RKIP postpones molecular damages and subsequent cardiac dysfunction in mice carrying mutant PLNR9C by correction of aberrant Ca2+-handling |
| title_sort | from ca2 dysregulation to heart failure β adrenoceptor activation by rkip postpones molecular damages and subsequent cardiac dysfunction in mice carrying mutant plnr9c by correction of aberrant ca2 handling |
| topic | Ca2+ dysregulation Mitochondrial and ER defects PLNR9C RKIP Heart failure |
| url | http://www.sciencedirect.com/science/article/pii/S1043661824005036 |
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