Mustroph, Julian and Sag, Can M. and Baehr, Felix and Schmidtmann, Anna-Lena and Gupta, Shamindra N. and Dietz, Alexander and Islam, M. M. Towhidul and Luecht, Charlotte and Beuthner, Bo Eric and Pabel, Steffen and Baier, Maria J. and El-Armouche, Ali and Sossalla, Samuel and Anderson, Mark E. and Moellmann, Julia and Lehrke, Michael and Marx, Nikolaus and Mohler, Peter J. and Bers, Donald M. and Unsoeld, Bernhard and He, Tao and Dewenter, Matthias and Backs, Johannes and Maier, Lars S. and Wagner, Stefan (2021) Loss of CASK Accelerates Heart Failure Development. CIRCULATION RESEARCH, 128 (8). pp. 1139-1155. ISSN 0009-7330, 1524-4571
Full text not available from this repository. (Request a copy)Abstract
Rationale: Increased myocardial activity of CaMKII (Ca/calmodulin-dependent kinase II) leads to heart failure and arrhythmias. In Drosophila neurons, interaction of CaMKII with CASK (Ca/CaM-dependent serine protein kinase) has been shown to inhibit CaMKII activity, but the consequences of this regulation for heart failure and ventricular arrhythmias are unknown. Objective: We hypothesize that CASK associates with CaMKII in human and mouse hearts thereby limiting CaMKII activity and that altering CASK expression in mice changes CaMKII activity accordingly, with functional consequences for contractile function and arrhythmias. Methods and Results: Immunoprecipitation revealed that CASK associates with CaMKII in human hearts. CASK expression is unaltered in heart failure but increased in patients with aortic stenosis. In mice, cardiomyocyte-specific knockout of CASK increased CaMKII-autophosphorylation at the stimulatory T287 site, but reduced phosphorylation at the inhibitory T305/306 site. Knockout of CASK mice showed increased CaMKII-dependent sarcoplasmic reticulum Ca leak, reduced sarcoplasmic reticulum Ca content, increased susceptibility to ventricular arrhythmias, greater loss of ejection fraction, and increased mortality after transverse aortic constriction. Intriguingly, stimulation of the cardiac glucagon-like peptide 1 receptor with exenatide increased CASK expression resulting in increased inhibitory CaMKII T305 phosphorylation, reduced CaMKII activity, and reduced sarcoplasmic reticulum Ca leak in wild type but not CASK-KO. Conclusions: CASK associates with CaMKII in the human heart. Knockout of CASK in mice increases CaMKII activity, leading to contractile dysfunction and arrhythmias. Increasing CASK expression reduces CaMKII activity, improves Ca handling and contractile function.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CA2+/CALMODULIN-DEPENDENT PROTEIN-KINASE; RETICULUM CA2+ LEAK; CARDIAC-HYPERTROPHY; CAMKII; CALCIUM; DELTA; CALMODULIN; AUTOPHOSPHORYLATION; PHOSPHORYLATION; ARRHYTHMIAS; calmodulin; heart failure; myocardium; neurons; sarcoplasmic reticulum |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 12 Sep 2022 06:54 |
| Last Modified: | 12 Sep 2022 06:54 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47121 |
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