Stretch current-induced abnormal impulses in CaMKIIδ knockout mouse ventricular myocytes.
Stretch current-induced abnormal impulses in CaMKIIδ knockout mouse ventricular myocytes.
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DOI：
10.1111/jce.12060
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发表时间：
2013-04
影响因子：
2.7
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Lai D;Xu L;Cheng J;Guilbert AB;Lim HJ;Fu G;Wang Y
CaMKII激活在心肌伸展的心力衰竭中是促心肌炎的。然而，CaMKII在牵张心室中的致心律失常作用尚未得到很好的理解。我们测试了从CaMKIIδ敲除（KO）小鼠左心室（LV）分离的肌细胞中牵张电流诱导的异常冲动，其中CaMKII活性降低了约62%。全细胞膜片钳记录动作电位，模拟牵张激活通道（SAC）电流诱发左心室肌细胞异常冲动。SAC激活未能诱导野生型（WT）心肌细胞的异常冲动，但稳定地产生早期后除极（埃兹）和KO心肌细胞的自律性，其中观察到L型钙通道（LTCC）电流（伊卡）增加和肌浆网（SR）Ca 2+漏和动作电位时程（APD）减少。CaMKII抑制剂AIP不抑制异常冲动，而低浓度的硝苯地平消除异常冲动而不缩短APD，这意味着伊卡促进牵张诱导的异常冲动。此外，LTCC开放剂S（-）Bay K 8644或异丙肾上腺素延长APD促进WT心室肌细胞的异常冲动诱导，即使在存在CaMKII抑制剂AIP的情况下，而K+通道阻断剂4-氨基吡啶延长APD促进KO心肌细胞的异常冲动诱导，但在WT心肌细胞中不存在。伊卡激活在牵张诱发的异常冲动中起着重要作用，APD延长仅在伊卡高度激活时才起致心律失常作用。在增加的伊卡激活，CaMKII抑制不能抑制异常的冲动诱导。
CaMKII activation is pro-arrhythmic in heart failure where myocardium is stretched. However, the arrhythmogenic role of CaMKII in stretched ventricle has not been well understood. We tested abnormal impulse inducibility by stretch current in myocytes isolated from CaMKIIδ knockout (KO) mouse left ventricle (LV) where CaMKII activity is reduced by ≈ 62%. Action potentials (APs) were recorded by whole-cell patch clamp, and abnormal impulses were induced in LV myocytes by a simulation of stretch-activated-channel (SAC) current. SAC activation failed to induce abnormal impulses in wild type (WT) myocytes but steadily produced early afterdepolarizations (EADs) and automaticity in KO myocytes in which an increase in L-type calcium channel (LTCC) current (ICa) and a reduction of sarcoplasmic reticulum (SR) Ca2+ leak and action potential duration (APD) were observed. The abnormal impulses were not suppressed by CaMKII inhibitor AIP whereas a low concentration of nifedipine eliminated abnormal impulses without shortening APD, implicating ICa in promoting stretch-induced abnormal impulses. In addition, APD prolongation by LTCC opener S(−)Bay K 8644 or isoproterenol facilitated abnormal impulse induction in WT ventricular myocytes even in the presence of CaMKII inhibitor AIP, whereas APD prolongation by K+ channel blocker 4-aminopyridine promoted abnormal impulses in KO myocytes but not in WT myocytes. ICa activation plays a central role in stretch-induced abnormal impulses and APD prolongation is arrhythmogenic only when ICa is highly activated. At increased ICa activation, CaMKII inhibition cannot suppress abnormal impulse induction.
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影响因子：
4.8
作者：
Wang, Yanggan;Tandan, Samvit;Hill, Joseph A.
通讯作者：
Hill, Joseph A.
影响因子：
37.8
作者：
Wu, YJ;Temple, J;Anderson, ME
通讯作者：
Anderson, ME
DOI：
10.1152/ajpheart.00484.2007
发表时间：
2008-04-01
影响因子：
4.8
作者：
Maltsev, Victor A.;Reznikov, Vitaliy;Undrovinas, Albertas
通讯作者：
Undrovinas, Albertas
DOI：
10.1111/j.1540-8167.2007.00864.x
发表时间：
2007-08-01
影响因子：
2.7
作者：
Wang, Yanggan;Cheng, Jun;Hill, Joseph A.
通讯作者：
Hill, Joseph A.
影响因子：
4.5
作者：
Kamkin, A;Kiseleva, I;Isenberg, G
通讯作者：
Isenberg, G