Reduced heterogeneous expression of Cx43 results in decreased Nav1.5 expression and reduced sodium current that accounts for arrhythmia vulnerability in conditional Cx43 knockout mice.
Reduced heterogeneous expression of Cx43 results in decreased Nav1.5 expression and reduced sodium current that accounts for arrhythmia vulnerability in conditional Cx43 knockout mice.
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DOI：
10.1016/j.hrthm.2011.11.025
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发表时间：
2012-04
期刊：
影响因子：
5.5
通讯作者：
van Rijen, Harold V.
中科院分区：
文献类型：
--
作者：
Jansen, John A.;Noorman, Maartje;Musa, Hassan;Stein, Mera;de Jong, Sanne;van der Nagel, Roel;Hund, Thomas J.;Mohler, Peter J.;Vos, Marc A.;van Veen, Toon A.;de Bakker, Jacques M.;Delmar, Mario;van Rijen, Harold V.
连接蛋白43 （Cx43）、钠通道（Nav1.5）表达减少和胶原蛋白表达增加（纤维化）是心脏脉冲传导的重要决定因素。为了研究这些因素在极低Cx43表达时的重要性和相互作用，我们用电生理和免疫组织化学方法比较了诱导性Cx43 KO小鼠伴和不伴室性心动过速（VT）的情况。他莫昔芬诱导Cx43CreER(T)/fl小鼠，2周后处死。对langendorff灌注心脏进行心外膜激活测绘，并检测心律失常易感性。将小鼠细分为VT+ (n=13)和VT - (n=10)，分析心脏组织Cx43、Nav1.5和纤维化。与VT -小鼠相比，VT+小鼠Cx43的表达降低，Cx43的全局异质性增加，而不是局部异质性。与VT -小鼠相比，VT+小鼠的nav1.5免疫反应蛋白表达降低，特别是在缺乏Cx43的位点。VT -和VT+小鼠的纤维化水平相似。与VT -小鼠相比，VT+小鼠的qrs持续时间增加，心外膜激活更分散。两组患者的有效不应期（ERP）相似。与右心室VT -心脏相比，过早刺激导致右心室VT+心脏的传导减慢更为严重。膜片钳分离大鼠心室肌细胞实验证实Cx43表达缺失与钠电流振幅降低相关。Cx43表达的全球异质性以及伴随的钠通道蛋白表达和钠电流的异质下调导致传导减慢和分散，从而使心脏对室性心律失常敏感。
Reduced Connexin43 (Cx43), sodium channel (Nav1.5) expression and increased collagen expression (fibrosis) are important determinants of impulse conduction in the heart. To study the importance and interaction of these factors at very low Cx43 expression, inducible Cx43 KO mice with and without inducible ventricular tachycardia (VT) were compared by electrophysiology and immunohistochemistry. Cx43CreER(T)/fl mice were induced with Tamoxifen and sacrificed after 2 weeks. Epicardial activation mapping was performed on Langendorff-perfused hearts, and arrhythmia vulnerability was tested. Mice were subdivided in VT+ (n=13) and VT− (n=10) and heart tissue was analyzed for Cx43, Nav1.5 and fibrosis. VT+ mice had decreased Cx43 expression with increased global, but not local, heterogeneity of Cx43, compared to VT− mice. Nav1.5-immunoreactive protein expression was reduced in VT+ versus VT− mice, specifically at sites devoid of Cx43. Levels of fibrosis were similar between VT− and VT+ mice. QRS-duration was increased and epicardial activation was more dispersed in VT+ mice than in VT− mice. The effective refractory period (ERP) was similar between both groups. Premature stimulation resulted in a more severe conduction slowing in VT+ compared to VT− hearts in the right ventricle. Separate patch clamp experiments in isolated rat ventricular myocytes confirmed that loss of Cx43 expression correlated with decreased sodium current amplitude. Global heterogeneity in Cx43 expression and concomitant heterogeneous downregulation of sodium channel protein expression and sodium current leads to slowed and dispersed conduction, which sensitizes the heart for ventricular arrhythmias.
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影响因子：
6
作者：
Peters, NS
通讯作者：
Peters, NS
影响因子：
18.2
作者：
Boulaksil, Mohamed;Winckels, Stephan K. G.;van Rijen, Harold V. M.
通讯作者：
van Rijen, Harold V. M.
影响因子：
20.1
作者：
Sato PY;Coombs W;Lin X;Nekrasova O;Green KJ;Isom LL;Taffet SM;Delmar M
通讯作者：
Delmar M
影响因子：
37.8
作者：
Gutstein, DE;Morley, GE;Fishman, GI
通讯作者：
Fishman, GI
影响因子：
20.1
作者：
Gutstein, DE;Morley, GE;Fishman, GI
通讯作者：
Fishman, GI