Mohamed, Belal A. and Hartmann, Nico and Tirilomis, Petros and Sekeres, Karolina and Li, Wener and Neef, Stefan and Richter, Claudia and Zeisberg, Elisabeth M. and Kattner, Lars and Didie, Michael and Guan, Kaomei and Schmitto, Jan D. and Lehnart, Stephan E. and Luther, Stefan and Voigt, Niels and Seidler, Tim and Sossalla, Samuel and Hasenfuss, Gerd and Toischer, Karl (2018) Sarcoplasmic reticulum calcium leak contributes to arrhythmia but not to heart failure progression. SCIENCE TRANSLATIONAL MEDICINE, 10 (458): eaan0724. ISSN 1946-6234, 1946-6242
Full text not available from this repository. (Request a copy)Abstract
Increased sarcoplasmic reticulum (SR) Ca2+ leak via the cardiac ryanodine receptor (RyR2) has been suggested to play a mechanistic role in the development of heart failure (HF) and cardiac arrhythmia. Mice treated with a selective RyR2 stabilizer, rycal S36, showed normalization of SR Ca2+ leak and improved survival in pressure overload (PO) and myocardial infarction (MI) models. The development of HF, measured by echocardiography and molecular markers, showed no difference in rycal S36-versus placebo-treated mice. Reduction of SR Ca2+ leak in the PO model by the rycal-unrelated RyR2 stabilizer dantrolene did not mitigate HF progression. Development of HF was not aggravated by increased SR Ca2+ leak due to RyR2 mutation (R2474S) in volume overload, an SR Ca2+ leakindependent HF model. Arrhythmia episodes were reduced by rycal S36 treatment in PO and MI mice in vivo and ex vivo in Langendorff-perfused hearts. Isolated cardiomyocytes from murine failing hearts and human ventricular failing and atrial nonfailing myocardium showed reductions in delayed afterdepolarizations, in spontaneous and induced Ca2+ waves, and in triggered activity in rycal S36 versus placebo cells, whereas the Ca2+ transient, SR Ca2+ load, SR Ca2+ adenosine triphosphatase function, and action potential duration were not affected. Rycal S36 treatment of human induced pluripotent stem cells isolated from a patient with catecholaminergic polymorphic ventricular tachycardia could rescue the leaky RyR2 receptor. These results suggest that SR Ca2+ leak does not primarily influence contractile HF progression, whereas rycal S36 treatment markedly reduces ventricular arrhythmias, thereby improving survival in mice.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CHANNEL RYANODINE RECEPTOR; POLYMORPHIC VENTRICULAR-TACHYCARDIA; PROTEIN-KINASE-II; CA2+ RELEASE; INTRACELLULAR CA2+; PRESSURE-OVERLOAD; IMPROVES; MICE; PHOSPHORYLATION; ATRIAL; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 13 Dec 2019 08:23 |
| Last Modified: | 13 Dec 2019 08:23 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13864 |
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