Phospholamban Knockout Breaks Arrhythmogenic Ca2+ Waves and Suppresses Catecholaminergic Polymorphic Ventricular Tachycardia in Mice
Por:
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
Publicada:
16 ago 2013
Resumen:
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.
Filiaciones:
Bai, YL:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 4N1, Canada
Jones, PP:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 4N1, Canada
Univ Otago, Dept Physiol, Dunedin 9016, New Zealand
Guo, JQ:
Univ Calgary, Dept Med Sci, Calgary, AB T2N 4N1, Canada
Zhong, XW:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 4N1, Canada
Clark, RB:
Univ Calgary, Fac Kinesiol, Calgary, AB T2N 4N1, Canada
Zhou, Q:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 4N1, Canada
Wang, RW:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 4N1, Canada
Vallmitjana, A:
Univ Politecn Cataluna, Dept Automat Control, Barcelona, Spain
Benitez, R:
Univ Politecn Cataluna, Dept Automat Control, Barcelona, Spain
Hove-Madsen, L:
Hosp Santa Creu & Sant Pau, Cardiovasc Res Ctr CSIC ICCC, Barcelona, Spain
Semeniuk, L:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 4N1, Canada
Guo, A:
Univ Iowa, Dept Internal Med, Carver Coll Med, Div Cardiovasc Med, Iowa City, IA 52242 USA
Song, LS:
Univ Iowa, Dept Internal Med, Carver Coll Med, Div Cardiovasc Med, Iowa City, IA 52242 USA
Duff, HJ:
Univ Calgary, Dept Med Sci, Calgary, AB T2N 4N1, Canada
Chen, SRW:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Physiol & Pharmacol, Calgary, AB T2N 4N1, Canada
Green Accepted, Bronze
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