Title:
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Phospholamban knockout breaks arrhythmogenic Ca2+ waves and suppresses catecholaminergic polymorphic ventricular tachycardia in mice
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Author:
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Bai, Yunlong; Jones, Peter; Guo, Jiqing; Zhong, Xiaowei; Clark, Robert; Zhou, Qiang; Wang, Ruiwu; Vallmitjana Lees, Alexander; Benítez Iglesias, Raúl; Hove-Madsen, Leif; Semeniuk, Lisa; Guo, Ang; Song, Long-Sheng; Duff, Henry J.; Chen, S.R. Wayne
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Other authors:
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Universitat Politècnica de Catalunya. Departament d'Enginyeria de Sistemes, Automàtica i Informàtica Industrial; Universitat Politècnica de Catalunya. NOLIN - Física No-Lineal i Sistemes Fora de l'Equilibri |
Abstract:
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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. |
Abstract:
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Peer Reviewed |
Subject(s):
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-Àrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::Bioinformàtica -Àrees temàtiques de la UPC::Ciències de la salut::Medicina::Medicina interna -Heart -- Diseases -- Animal models -Cardiac dynamics -Calcium handling -quantitative physiology -biomedical signal processing -Cor -- Malalties -- Tractament |
Rights:
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Document type:
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Article - Published version Article |
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