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

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

doi:10.1016/j.phrs.2024.107558

From Ca²⁺ dysregulation to heart failure: β-adrenoceptor activation by RKIP postpones molecular damages and subsequent cardiac dysfunction in mice carrying mutant PLN^R9C by correction of aberrant Ca²⁺-handling

Pharmacol Res. 2024 Dec 30:211:107558. doi: 10.1016/j.phrs.2024.107558. Online ahead of print.

Authors

Theresa Brand¹, Bettina Tanitha Baumgarten², Sabrina Denzinger¹, Yvonne Reinders², Miriam Kleindl², Constanze Schanbacher¹, Florian Funk³, Nilgün Gedik⁴, Mahmood Jabbasseh³, Petra Kleinbongard⁴, Jan Dudek⁵, Julia Szendroedi⁶, Elen Tolstik², Kai Schuh⁷, Martina Krüger⁸, Dobromir Dobrev⁹, Friederike Cuello¹⁰, Albert Sickmann², Joachim P Schmitt¹¹, Kristina Lorenz¹²

Affiliations

¹ Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Str. 9, Würzburg 97078, Germany.
² Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Bunsen-Kirchhoff-Str. 11, Dortmund 44139, Germany.
³ Institute 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.
⁴ Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Hufelandstr. 55, Essen 45122, Germany.
⁵ Comprehensive Heart Failure Center, University Hospital of Würzburg, Am Schwarzenberg 15, Würzburg 97078, Germany.
⁶ Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany.
⁷ Institute of Physiology, University of Würzburg, Würzburg, Germany.
⁸ Cardiovascular 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, Germany.
⁹ Institute 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, Canada.
¹⁰ DZHK (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, Germany.
¹¹ Institute 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. Electronic address: [email protected].
¹² 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. Electronic address: [email protected].

PMID: 39742932
DOI: 10.1016/j.phrs.2024.107558

Abstract

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 (PLN^R9C-tg) causing severe HF due to a reduction in Ca²⁺ reuptake into the sarco(endo)plasmic reticulum (SR). PLN^R9C-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 Ca^{2 +} 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.

Keywords: Ca(2+) dysregulation; Heart failure; Mitochondrial and ER defects; PLN(R9C); RKIP.