Angiotensin II induces afterdepolarizations via reactive oxygen species and calmodulin kinase II signaling.
Angiotensin II induces afterdepolarizations via reactive oxygen species and calmodulin kinase II signaling.
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DOI：
10.1016/j.yjmcc.2010.11.001
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发表时间：
2011-01
影响因子：
5
通讯作者：
Xie LH
中科院分区：
文献类型：
--
作者：
Zhao Z;Fefelova N;Shanmugam M;Bishara P;Babu GJ;Xie LH
肾素-血管紧张素系统抑制剂可显著降低心律失常的发生率。然而，其潜在的机制尚不清楚。我们的目的是验证Ang II通过烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶- ros -钙调素激酶II （CaMKII）途径诱导早期后去极化（EADs）和触发活性（TAs）的假设。对负载ROS染料的兔离体肌细胞进行ROS生成分析。Ang II（1 - 2µM）增加了肌细胞的ROS荧光，而这种荧光分别被Ang II型1受体阻断剂氯沙坦、NADPH氧化酶抑制剂罗经肽和抗氧化剂MnTMPyP所消除。用穿孔膜片钳技术记录动作电位。在1~2µM灌注后15.8±1.6 min， 41个细胞中有27个（66%）出现了EADs。用氯沙坦、罗布麻碱或trolox消除Angⅱ诱导的EADs。CaMK II抑制剂KN-93 （n=6）和抑制肽（AIP） （n=4）也能抑制Ang II诱导的EADs，而无活性类似物KN-92则没有。硝苯地平是L型钙电流的阻滞剂（ICa，L），雷诺嗪是晚期钠电流的抑制剂（INa），可以消除Ang ii诱导的EADs。采用电压箝位法评价了angii对主要膜电流的影响。相同浓度的Ang II对总外向K+电流无显著影响，但增强了ICa。L和晚期INa，氯沙坦、罗布麻碱、曲洛克斯或KN-93对其有减弱作用。我们得出结论，Ang II通过NADPH氧化酶产生细胞内ROS，激活CaMKII，增强ICa，L和晚期INa，从而诱导EADs。这些结果为肾素-血管紧张素系统与心律失常之间的联系提供了证据。
Renin-angiotensin system inhibitors significantly reduce the incidence of arrhythmias. However, the underlying mechanism(s) is not well understood. We aim to test the hypothesis that Ang II induces early afterdepolarizations (EADs) and triggered activities (TAs) via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-ROS-calmodulin kinase II (CaMKII) pathway. ROS production was analyzed in the isolated rabbit myocytes loaded with ROS dye. Ang II (1–2 µM) increased ROS fluorescence in myocytes, which was abolished by Ang II type 1 receptor blocker losartan, NADPH oxidase inhibitor apocynin, and antioxidant MnTMPyP, respectively. Action potentials were recorded using the perforated patch-clamp technique. EADs emerged in 27 out of 41 (66%) cells at 15.8 ± 1.6 min after Ang II (1~2 µM) perfusion. Ang II-induced EADs were eliminated by losartan, apocynin, or trolox. The CaMK II inhibitor KN-93 (n=6) and inhibitory peptide (AIP) (n=4) also suppressed Ang II-induced EADs, whereas the inactive analogue KN-92 did not. Nifedipine, a blocker of L-type Ca current (ICa,L), or ranolazine, an inhibitor of late Na current (INa), abolished Ang II-induced EADs. The effects of Ang II on major membrane currents were evaluated using voltage clamp. While Ang II at same concentrations had no significant effect on total outward K+ current, it enhanced ICa.L and late INa, which were attenuated by losartan, apocynin, trolox, or KN-93. We conclude that Ang II induces EADs via intracellular ROS production through NADPH oxidase, activation of CaMKII, and enhancement of ICa,L and late INa. These results provide evidence supporting a link between renin-angiotensin system and cardiac arrhythmias.
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DOI：
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发表时间：
2009-10
影响因子：
4
作者：
Aon, M. A.;Cortassa, S.;Akar, F. G.;Brown, D. A.;Zhou, L.;O'Rourke, B.
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发表时间：
2007-08-01
影响因子：
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