Resveratrol protects rabbit ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca2+ overload
Resveratrol protects rabbit ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca2+ overload
复制标题
白藜芦醇保护兔心室肌细胞免受氧化应激诱导的心律失常活动和 Ca2+ 超载
DOI：
10.1038/aps.2013.82
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发表时间：
2013-09-01
影响因子：
8.2
通讯作者：
Li, Yi-gang
中科院分区：
文献类型：
--
作者：
Li, Wei;Wang, Yue-peng;Li, Yi-gang
目的：研究白藜芦醇能否抑制氧化应激诱导的心肌细胞心律失常活性和钙超载，并探讨其机制。方法：采用过氧化氢(过氧化氢，200mMol/L)诱导兔心肌细胞氧化应激。同时记录细胞缩短和钙瞬变，以检测致心律失常活动和测量细胞内钙离子([Ca~(2+)](I))。用CaMKII试剂盒或Western blotting分析CaMKII活性。结果：H_2O_2可显著延长0.16 Hz和0.5 Hz起搏心肌细胞的钙瞬变时程(CaTD)，并诱发早后除极(EAD)样和延迟后除极(DAD)样心律失常。应用白藜芦醇(30或50 mU/L)可剂量依赖性地抑制H_2O_2诱导的EAD样致心律失常活动，并减弱CaTd延长。白藜芦醇(50 mU/L)能有效抑制H_2O_2诱发的EAD和DAD样致心律失常。此外，白藜芦醇还能显著抑制H_2O_2诱导的舒张期[Ca~(2+)](I)蓄积，防止心肌细胞过度收缩。在全细胞记录研究中，H_2O_2显著增强心肌细胞晚期钠电流(I-Na，I-L)和L型钙电流(I-Ca，I-L)，白藜芦醇可显著抑制或阻止这两种电流。结论：白藜芦醇通过抑制I-Na、I-L/I-Ca、I-L，减少ROS的产生，阻止CaMKII的激活，从而保护心肌细胞免受氧化应激所致的心律失常和钙超载的影响。
Aim: To investigate whether resveratrol suppressed oxidative stress-induced arrhythmogenic activity and Ca2+ overload in ventricular myocytes and to explore the underlying mechanisms.Methods: Hydrogen peroxide (H2O2, 200 mu mol/L)) was used to induce oxidative stress in rabbit ventricular myocytes. Cell shortening and calcium transients were simultaneously recorded to detect arrhythmogenic activity and to measure intracellular Ca2+ ([Ca2+](i)). Ca2+/calmodulin-dependent protein kinases II (CaMKII) activity was measured using a CaMKII kit or Western blotting analysis. Voltage-activated Na+ and Ca2+ currents were examined using whole-cell recording in myocytes.Results: H2O2 markedly prolonged Ca2+ transient duration (CaTD), and induced early afterdepolarization (EAD)-like and delayed afterdepolarization (DAD)-like arrhythmogenic activity in myocytes paced at 0.16 Hz or 0.5 Hz. Application of resveratrol (30 or 50 mu mol/L) dose-dependently suppressed H2O2-induced EAD-like arrhythmogenic activity and attenuated CaTD prolongation. Co-treatment with resveratrol (50 mu mol/L) effectively prevented both EAD-like and DAD-like arrhythmogenic activity induced by H2O2. In addition, resveratrol markedly blunted H2O2-induced diastolic [Ca2+](i) accumulation and prevented the myocytes from developing hypercontracture. In whole-cell recording studies, H2O2 significantly enhanced the late Na+ current (I-Na,I-L) and L-type Ca2+ current (I-Ca,I-L) in myocytes, which were dramatically suppressed or prevented by resveratrol. Furthermore, H2O2-induced ROS production and CaMKII activation were significantly prevented by resveratrol.Conclusion: Resveratrol protects ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca2+ overload through inhibition of I-Na,I-L/I-Ca,I-L, reduction of ROS generation, and prevention of CaMKII activation.