Suppression of ryanodine receptor function prolongs Ca2+ release refractoriness and promotes cardiac alternans in intact hearts
Por:
Zhong, XW, Sun, B, Vallmitjana, A, Mi, T, Guo, WT, Ni, MK, Wang, RW, Guo, A, Duff, HJ, Gillis, AM, Song, LS, Hove-Madsen, L, Benitez, R, Chen, SRW
Publicada:
1 nov 2016
Resumen:
Beat-to-beat alternations in the amplitude of the cytosolic Ca2+ transient (Ca2+ alternans) are thought to be the primary cause of cardiac alternans that can lead to cardiac arrhythmias and sudden death. Despite its important role in arrhythmogenesis, the mechanism underlying Ca2+ alternans remains poorly understood. Here, we investigated the role of cardiac ryanodine receptor (RyR2), the major Ca2+ release channel responsible for cytosolic Ca2+ transients, in cardiac alternans. Using a unique mouse model harboring a suppression- of-function (SOF) RyR2 mutation (E4872Q), we assessed the effect of genetically suppressing RyR2 function on Ca2+ and action potential duration (APD) alternans in intact hearts, and electrocardiogram (ECG) alternans in vivo. We found that RyR2-SOF hearts displayed prolonged sarcoplasmic reticulum Ca2+ release refractoriness and enhanced propensity for Ca2+ alternans. RyR2-SOF hearts/mice also exhibited increased propensity for APD and ECG alternans. Caffeine, which enhances RyR2 activity and the propensity for catecholaminergic polymorphic ventricular tachycardia (CPVT), suppressed Ca2+ alternans in RyR2-SOF hearts, whereas carvedilol, a beta-blocker that suppresses RyR2 activity and CPVT, promoted Ca2+ alternans in these hearts. Thus, RyR2 function is an important determinant of Ca2+, APD, and ECG alternans. Our data also indicate that the activity of RyR2 influences the propensity for cardiac alternans and CPVT in an opposite manner. Therefore, overly suppressing or enhancing RyR2 function is pro-arrhythmic.
Filiaciones:
Zhong, XW:
Univ Calgary, Dept Physiol & Pharmacol, Libin Cardiovasc Inst Alberta, 3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Sun, B:
Univ Calgary, Dept Physiol & Pharmacol, Libin Cardiovasc Inst Alberta, 3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Vallmitjana, A:
Univ Politecn Cataluna, Dept Automat Control, ES-08034 Barcelona, Spain
Mi, T:
Univ Calgary, Dept Physiol & Pharmacol, Libin Cardiovasc Inst Alberta, 3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Huazhong Univ Sci & Technol, Dept Cardiol, Tongji Hosp, Tongji Med Sch, Wuhan 430030, Peoples R China
Guo, WT:
Univ Calgary, Dept Physiol & Pharmacol, Libin Cardiovasc Inst Alberta, 3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Ni, MK:
Univ Calgary, Dept Physiol & Pharmacol, Libin Cardiovasc Inst Alberta, 3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Wang, RW:
Univ Calgary, Dept Physiol & Pharmacol, Libin Cardiovasc Inst Alberta, 3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Guo, A:
Univ Iowa, Carver Coll Med, Dept Internal Med, Div Cardiovasc Med, Iowa City, IA 52242 USA
Duff, HJ:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Cardiac Sci, Calgary, AB T2N 1N4, Canada
Gillis, AM:
Univ Calgary, Libin Cardiovasc Inst Alberta, Dept Cardiac Sci, Calgary, AB T2N 1N4, Canada
Song, LS:
Univ Iowa, Carver Coll Med, Dept Internal Med, Div Cardiovasc Med, Iowa City, IA 52242 USA
Hove-Madsen, L:
ICCC, Cardiovasc Res Ctr, CSIC, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, IIB St Pau, Barcelona 08025, Spain
Benitez, R:
Univ Politecn Cataluna, Dept Automat Control, ES-08034 Barcelona, Spain
Chen, SRW:
Univ Calgary, Dept Physiol & Pharmacol, Libin Cardiovasc Inst Alberta, 3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Green Accepted
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