Cardiac-restricted angiotensin-converting enzyme overexpression causes conduction defects and connexin dysregulation
Cardiac-restricted angiotensin-converting enzyme overexpression causes conduction defects and connexin dysregulation
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DOI：
10.1152/ajpheart.00684.2006
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发表时间：
2007-07-01
影响因子：
4.8
通讯作者：
Dudley, Samuel C., Jr.
中科院分区：
文献类型：
--
作者：
Kasi, Vijaykumar S.;Xiao, Hong D.;Dudley, Samuel C., Jr.
肾素-血管紧张素系统(RAS)激活与猝死风险增加有关。以前，我们利用心脏限制性血管紧张素转换酶(ACE)的过度表达来构建RAS激活的小鼠模型。这些ACE 8/8小鼠过早而突然死亡。在这里，我们研究了心脏电生理异常，这些异常可能导致该模型的早期死亡。在ACE 8/8小鼠中，体表心电图电压降低。心内电图显示，与野生型(WT)对照组相比，房室电位波幅分别为11%和24%。与WT组相比，ACE8/8组小鼠的房室间期、房室间期和房室间期分别延长2.8、2.6和3.9倍。仅ACE8/8小鼠出现不同程度的房室结传导阻滞。心内电生理研究表明，WT和杂合子(HZ)小鼠是不可诱发的，而ACE8/8小鼠中83%的小鼠出现了阵发性起搏的室性心动过速。与WT小鼠相比，ACE8/8组小鼠心房连接蛋白40(Cx40)和连接蛋白43(Cx43)蛋白表达水平、心肌Cx43蛋白水平、心房和心室Cx40基因丰度、心肌Cx43基因丰度和心房钠(+)通道(SCN5A)基因丰度均显著降低。ACE8/8小鼠表现出心肌Cx43去磷酸化。心房和心室L型钙通道、Kv4.2K(+)通道α亚单位、Cx45mRNA丰度和心室钠电流峰值在组间差异无统计学意义。在离体心标本中，连接蛋白阻滞剂1-庚醇(0.5 mM)产生与ACE 8/8小鼠相似的电生理表型。因此，心脏特异性ACE的过度表达导致连接蛋白的变化，这些变化与低压电活动、传导缺陷和诱导性室性心律失常的表型一致。这些结果可能有助于解释RAS激活状态下心律失常风险的增加，例如心力衰竭。
Renin-angiotensin (RAS) system activation is associated with an increased risk of sudden death. Previously, we used cardiac-restricted angiotensin-converting enzyme (ACE) overexpression to construct a mouse model of RAS activation. These ACE 8/8 mice die prematurely and abruptly. Here, we have investigated cardiac electrophysiological abnormalities that may contribute to early mortality in this model. In ACE 8/8 mice, surface ECG voltages are reduced. Intracardiac electrograms showed atrial and ventricular potential amplitudes of 11% and 24% compared with matched wild-type (WT) controls. The atrioventricular (AV), atrio-Hisian (AH), and Hisian-ventricular (HV) intervals were prolonged 2.8-, 2.6-, and 3.9-fold, respectively, in ACE 8/8 vs. WT mice. Various degrees of AV nodal block were present only in ACE 8/8 mice. Intracardiac electrophysiology studies demonstrated that WT and heterozygote (HZ) mice were noninducible, whereas 83% of ACE 8/8 mice demonstrated ventricular tachycardia with burst pacing. Atrial connexin 40 (Cx40) and connexin 43 (Cx43) protein levels, ventricular Cx43 protein level, atrial and ventricular Cx40 mRNA abundances, ventricular Cx43 mRNA abundance, and atrial and ventricular cardiac Na(+) channel (Scn5a) mRNA abundances were reduced in ACE 8/8 compared with WT mice. ACE 8/8 mice demonstrated ventricular Cx43 dephosphorylation. Atrial and ventricular L-type Ca(2+) channel, Kv4.2 K(+) channel alpha-subunit, and Cx45 mRNA abundances and the peak ventricular Na(+)-current did not differ between the groups. In isolated heart preparations, a connexin blocker, 1-heptanol (0.5 mM), produced an electrophysiological phenotype similar to that seen in ACE 8/8 mice. Therefore, cardiac-specific ACE overexpression resulted in changes in connexins consistent with the phenotype of low-voltage electrical activity, conduction defects, and induced ventricular arrhythmia. These results may help explain the increased risk of arrhythmia in states of RAS activation such as heart failure.