Deletion of FoxO1 leads to shortening of QRS by increasing Na(+) channel activity through enhanced expression of both cardiac NaV1.5 and β3 subunit.
Deletion of FoxO1 leads to shortening of QRS by increasing Na(+) channel activity through enhanced expression of both cardiac NaV1.5 and β3 subunit.
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DOI：
10.1016/j.yjmcc.2014.06.006
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发表时间：
2014-09
影响因子：
5
通讯作者：
Xu, Haodong
中科院分区：
文献类型：
--
作者：
Cai, Benzhi;Wang, Ning;Mao, Weike;You, Tao;Lu, Yan;Li, Xiang;Li, Faqian;Xu, Haodong
我们的体外研究表明，转录因子Forkhead box protein O 1（FoxO 1）通过改变HL-1心肌细胞SCN 5a的启动子活性，负性调节心脏Na+通道的主要α亚基NaV1.5的表达。FoxO 1在调节心脏NaV1.5表达中的体内作用仍然未知。本研究旨在明确FoxO 1在小鼠心室肌细胞NaV1.5表达和心肌Na+通道活性调节中的作用，并评估心脏FoxO 1缺失小鼠的心脏电生理表型。通过聚合酶链反应（PCR）证实了他莫昔芬诱导的心脏特异性FoxO 1缺失。通过超声心动图和单个心室细胞电容分别评估，心脏FoxO 1缺失未导致心脏功能变化或肥大。Western blotting结果显示FoxO 1基因缺失的小鼠心肌FoxO 1蛋白表达显著降低，而NaV1.5蛋白表达显著升高。逆转录-PCR（RT-PCR）显示FoxO 1缺失导致NaV1.5和Na+通道亚基β3 mRNA的增加，但不导致β1、2、4或连接蛋白43的增加。完整的膜片钳记录表明，FoxO 1缺失可显着增强心脏Na+电流，而不影响稳态激活和失活，导致小鼠心室肌细胞动作电位加速去极化。心电图记录显示，心脏FoxO 1缺失的清醒和无约束小鼠的QRS波群明显缩短，P波振幅明显增加。NaV1.5表达在心肌梗死小鼠的梗死周围（边缘区）减少，FoxO 1在慢性缺血的人心脏的心肌细胞核中积累。我们的研究结果表明，FoxO 1在调节心脏NaV1.5和β3亚基的表达以及Na+通道活性中起重要作用，并且FoxO 1参与了缺血性心脏病NaV1.5表达的调节。
Our in vitro studies revealed that a transcription factor, Forkhead box protein O1 (FoxO1), negatively regulates the expression of NaV1.5, a main α subunit of the cardiac Na+ channel, by altering the promoter activity of SCN5a in HL-1 cardiomyocytes. The in vivo role of FoxO1 in the regulation of cardiac NaV1.5 expression remains unknown. The present study aimed to define the role of FoxO1 in the regulation of NaV1.5 expression and cardiac Na+ channel activity in mouse ventricular cardiomyocytes and assess the cardiac electrophysiological phenotype of mice with cardiac FoxO1 deletion. Tamoxifen-induced and cardiac-specific FoxO1 deletion was confirmed by polymerase chain reaction (PCR). Cardiac FoxO1 deletion failed to result in either cardiac functional changes or hypertrophy as assessed by echocardiography and individual ventricular cell capacitances, respectively. Western blotting showed that FoxO1 was significantly decreased while NaV1.5 protein level was significantly increased in mouse hearts with FoxO1 deletion. Reverse transcription-PCR (RT-PCR) revealed that FoxO1 deletion led to an increase in NaV1.5 and Na+ channel subunit β3 mRNA, but not β1, 2, 4, or connexin 43. Whole patch-clamp recordings demonstrated that cardiac Na+ currents were significantly augmented by FoxO1 deletion without affecting the steady-state activation and inactivation, leading to accelerated depolarization of action potentials in mouse ventricular cardiomyocytes. Electrocardiogram recordings showed that the QRS complex was significantly shortened and P wave amplitude was significantly increased in conscious and unrestrained mice with cardiac FoxO1 deletion. NaV1.5 expression was decreased in the peri-infarct (border-zone) of mice with myocardial infarction and FoxO1 accumulated in the cardiomyocyte nuclei of chronic ischemic human hearts. Our findings indicate that FoxO1 plays an important role in the regulation of NaV1.5 and β3 subunit expression as well as Na+ channel activity in the heart and that FoxO1 is involved in the modulation of NaV1.5 expression in ischemic heart disease.
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影响因子：
3.7
作者：
Leoni AL;Gavillet B;Rougier JS;Marionneau C;Probst V;Le Scouarnec S;Schott JJ;Demolombe S;Bruneval P;Huang CL;Colledge WH;Grace AA;Le Marec H;Wilde AA;Mohler PJ;Escande D;Abriel H;Charpentier F
通讯作者：
Charpentier F
DOI：
10.1073/pnas.0403711101
发表时间：
2004-12-14
影响因子：
11.1
作者：
Mohler, PJ;Rivolta, I;Bennett, V
通讯作者：
Bennett, V
影响因子：
4.5
作者：
Guzadhur, Laila;Pearcey, Sarah M.;Huang, Christopher L. -H.
通讯作者：
Huang, Christopher L. -H.
影响因子：
20.1
作者：
Gavillet, Bruno;Rougier, Jean-Sebastien;Abriel, Hugues
通讯作者：
Abriel, Hugues
影响因子：
20.1
作者：
Evans-Anderson, Heather J.;Alfieri, Christina M.;Yutzey, Katherine E.
通讯作者：
Yutzey, Katherine E.