Journal article
Phospholamban Knockout Breaks Arrhythmogenic Ca2+ Waves and Suppresses Catecholaminergic Polymorphic Ventricular Tachycardia in Mice
Circulation research, Vol.113(5), pp.517-526
08/16/2013
DOI: 10.1161/CIRCRESAHA.113.301678
PMCID: PMC3864692
PMID: 23856523
Abstract
Rationale:
Phospholamban (PLN) is an inhibitor of cardiac sarco(endo)plasmic reticulum Ca2+ ATPase. PLN knockout (PLN-KO) enhances sarcoplasmic reticulum Ca2+ load and Ca2+ leak. Conversely, PLN-KO accelerates Ca2+ sequestration and aborts arrhythmogenic spontaneous Ca2+ waves (SCWs). An important question is whether these seemingly paradoxical effects of PLN-KO exacerbate or protect against Ca2+-triggered arrhythmias.
Objective:
We investigate the impact of PLN-KO on SCWs, triggered activities, and stress-induced ventricular tachyarrhythmias (VTs) in a mouse model of cardiac ryanodine-receptor (RyR2)-linked catecholaminergic polymorphic VT.
Methods and Results:
We generated a PLN-deficient, RyR2-mutant mouse model (PLN−/−/RyR2-R4496C+/−) by crossbreeding PLN-KO mice with catecholaminergic polymorphic VT–associated RyR2-R4496C mutant mice. Ca2+ imaging and patch-clamp recording revealed cell-wide propagating SCWs and triggered activities in RyR2-R4496C+/− ventricular myocytes during sarcoplasmic reticulum Ca2+ overload. PLN-KO fragmented these cell-wide SCWs into mini-waves and Ca2+ sparks and suppressed the triggered activities evoked by sarcoplasmic reticulum Ca2+ overload. Importantly, these effects of PLN-KO were reverted by partially inhibiting sarco(endo)plasmic reticulum Ca2+ ATPase with 2,5-di-tert-butylhydroquinone. However, Bay K, caffeine, or Li+ failed to convert mini-waves to cell-wide SCWs in PLN−/−/RyR2-R4496C+/− ventricular myocytes. Furthermore, ECG analysis showed that PLN-KO mice are not susceptible to stress-induced VTs. On the contrary, PLN-KO protected RyR2-R4496C mutant mice from stress-induced VTs.
Conclusions:
Our results demonstrate that despite severe sarcoplasmic reticulum Ca2+ leak, PLN-KO suppresses triggered activities and stress-induced VTs in a mouse model of catecholaminergic polymorphic VT. These data suggest that breaking up cell-wide propagating SCWs by enhancing Ca2+ sequestration represents an effective approach for suppressing Ca2+-triggered arrhythmias.
Details
- Title: Subtitle
- Phospholamban Knockout Breaks Arrhythmogenic Ca2+ Waves and Suppresses Catecholaminergic Polymorphic Ventricular Tachycardia in Mice
- Creators
- Yunlong Bai - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaPeter P Jones - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaJiqing Guo - Department of Medical Sciences, University of CalgaryXiaowei Zhong - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaRobert B Clark - Faculty of Kinesiology, University of CalgaryQiang Zhou - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaRuiwu Wang - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaAlexander Vallmitjana - Department of Automatic Control, Universitat Politècnica de Catalunya, BarcelonaRaul Benitez - Department of Automatic Control, Universitat Politècnica de Catalunya, BarcelonaLeif Hove-Madsen - Cardiovascular Research Centre CSIC-ICCC, Hospital de Sant Pau, Barcelona, SpainLisa Semeniuk - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, CanadaAng Guo - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IowaLong-Sheng Song - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IowaHenry J Duff - Department of Medical Sciences, University of CalgaryS.R. Wayne Chen - Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.113(5), pp.517-526
- DOI
- 10.1161/CIRCRESAHA.113.301678
- PMID
- 23856523
- PMCID
- PMC3864692
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Grant note
- R01 HL075210 || HL / National Heart, Lung, and Blood Institute : NHLBI
- Language
- English
- Date published
- 08/16/2013
- Academic Unit
- Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984094711702771
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