Reduced sarcoplasmic reticulum Ca2+ pump activity is antiarrhythmic in ischemic cardiomyopathy.
Reduced sarcoplasmic reticulum Ca2+ pump activity is antiarrhythmic in ischemic cardiomyopathy.
复制标题
肌浆网 Ca2 泵活性降低在缺血性心肌病中具有抗心律失常作用。
DOI：
10.1016/j.hrthm.2022.08.022
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发表时间：
2022
期刊：
影响因子：
5.5
通讯作者：
DudleyJr,SamuelC
中科院分区：
文献类型：
--
作者：
Xie,An;Liu,Hong;Kang,Gyeoung-Jin;Feng,Feng;DudleyJr,SamuelC
An arrhythmic mechanism seen only in heart failure (HF) that involves increased mitochondrial Ca 2+ handling, selective transfer of Ca 2+ to the sarcoplasmic reticulum (SR), and SR Ca 2+ leak. Modeling suggests mitochondrial Ca 2+ transfer to the SR via sarco/endoplasmic reticulum Ca 2+-ATPase 2a (SERCA2a) is crucial to this arrhythmic mechanism. Here, we tested the role of SERCA2a in arrhythmias during ischemic HF. Myocardial infarction (MI) was induced in wild type (Wt) and SERCA2a heterozygous knockdown (SERCA+/-) mice. SERCA+/-did not affect cardiac systolic and diastolic functions. Moreover, there were no significant changes in cardiac cellular diastolic or systolic functions, despite a significantly delayed decay of the cytoplasmic Ca 2+ transients compared to Wt. After MI, SERCA+/-MI mice shown significant shortening a decreased QTc and less ventricular tachycardia compared to those in Wt MI mice. At the cellular level, SERCA+/-MI cardiomyocytes showed a reduced APD90 and reduced triggered activity when compared to Wt MI cardiomyocytes. Ca 2+ sparks recorded from Wt MI cardiomyocytes were increased significantly than those in SERCA+/-MI cardiomyocytes. The expression of calsequestrin was substantially upregulated in SERCA+/-MI mice while there was no prominent alteration in Wt MI mice. Consistent with this, SR Ca 2+ content in Wt MI mouse cardiomyocytes was significantly higher than that in SERCA+/-MI mouse cardiomyocytes. In addition, the expression of FK506 binding protein (FKBP12. 6), which can stabilize RyR2, was unchanged. Mitochondrial protein tyrosine phosphatase-interacting protein-51 (PTPIP51), which can regulate mitochondria-SR associations, increased in Wt MI mice and was decreased in SERCA+/-MI mice. This alteration was consistent with electronic microscope data that mitochondria-SR contact increased in SERCA+/-MI mice. These results suggests that SERCA2a knockdown can be antiarrhythmic risk during ischemic HF by reducing SR-mitochondrial interactions and SR Ca 2+ load.
