Phospholamban Knockout Breaks Arrhythmogenic Ca2+ Waves and Suppresses Catecholaminergic Polymorphic Ventricular Tachycardia in Mice

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 q...

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Bibliographic Details
Authors: Bai, YL, Jones, PP, Guo, JQ, Zhong, XW, Clark, RB, Zhou, Q, Wang, RW, Vallmitjana, A, Benitez, R, Hove-Madsen, L, Semeniuk, L, Guo, A, Song, LS, Duff, HJ, Chen, SRW
Format: article
Status:Published version
Publication Date:2013
Country:España
Institution:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repository:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p9748
Online Access:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=9748
Access Level:Open access
Keyword:Ca2+ leak
Ca2+-triggered arrhythmias
Ca2+ waves
phospholamban
ryanodine receptor calcium release channel
sarcoplasmic reticulum
Description
Summary: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.

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