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AMPKα2 缺乏通过β-肾上腺素能受体信号增强小鼠室性心律失常易感性。

AMPKα2 deficiency enhanced susceptibility to ventricular arrhythmias in mice by the role of β-adrenoceptor signaling.

机构信息

1 Departments of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.

2 Department of Gerontology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.

出版信息

Exp Biol Med (Maywood). 2018 May;243(8):708-714. doi: 10.1177/1535370218767389. Epub 2018 Mar 29.

Abstract

AMP-activated protein kinase-α2 is the main catalytic subunit of the heart, which is mainly located in cardiac myocytes. The effect of AMP-activated protein kinase-α2 on the cardiac electrophysiology is barely studied. From the previous study, it is possible that AMP-activated protein kinase-α2 may have some effect on the electrophysiology of the heart. To prove the hypothesis, we used the AMP-activated protein kinase-α2 knockout (AMPKα2) mice to estimate the electrophysiological characteristics of AMPKα2 mice and try to find the mechanism between them. We used AMP-activated protein kinase-α2 gene knockout (AMPKα2) mice and control wild-type mice as the experimental animals. In the experiment, we measured the monophasic action potential duration and test the inducibility to ventricular arrhythmia in isolated mice heart with and without β-adrenoceptor antagonist metoprolol. Meanwhile, plasma concentration of catecholamine was collected. We found that AMPKα2 significantly shortened 90% repolarization of monophasic action potential (MAP) (MAPD than wild-type (47.4 ± 2.6 ms vs. 55.5 ± 2.4 ms, n = 10, P < 0.05) and were more vulnerable to be induced to ventricular arrhythmias (70% (7/10) vs. 10% (1/10), P < 0.05), accompanied by the higher concentration of catecholamine (epinephrine: 1.75 ± 0.18 nmol/L vs. 0.68 ± 0.10 nmol/L n = 10, P < 0.05; norepinephrine: 9.56 ± 0.71 nmol/L vs. 2.52 ± 0.31 nmol/L n = 10, P < 0.05). The shortening of MAPD and increased inducibility to ventricular arrhythmias of AMPKα2 could almost be abolished when perfusion with β-adrenoceptor antagonist metoprolol. It indicated that the β-adrenoceptor activation resulting from catecholamine release was mainly responsible for the relating changes of electrophysiology of AMPKα2. It had great clinical significance, as in patients who had problem with AMP-activated protein kinase-α2 gene, we might use β-adrenoceptor antagonists as the prevention of arrhythmias in future. Impact statement As far as we know, this is the first time the role of AMP-activated protein kinase-α2 (AMPKα2) on the cardiac electrophysiology is explored, and we found that the β-adrenoceptor activation resulting from catecholamine release was mainly responsible for the changes of electrophysiology related to the absence of AMPKα2. This has great clinical significance, as in patients who have problems with AMPKα2 gene, we may use β-adrenoceptor antagonists for the prevention of arrhythmias in future.

摘要

AMP 激活的蛋白激酶-α2 是心脏的主要催化亚基,主要位于心肌细胞中。AMP 激活的蛋白激酶-α2 对心脏电生理学的影响几乎没有研究。从之前的研究中可以看出,AMP 激活的蛋白激酶-α2 可能对心脏电生理学有一定的影响。为了证明这一假说,我们使用 AMP 激活的蛋白激酶-α2 基因敲除(AMPKα2)小鼠来估计 AMPKα2 小鼠的电生理特征,并试图找出它们之间的机制。我们使用 AMP 激活的蛋白激酶-α2 基因敲除(AMPKα2)小鼠和对照野生型小鼠作为实验动物。在实验中,我们测量了单相动作电位时程,并在有无β-肾上腺素能受体拮抗剂美托洛尔的情况下,测试了分离的小鼠心脏诱发室性心律失常的能力。同时,收集了血浆儿茶酚胺浓度。我们发现,AMPKα2 显著缩短了单相动作电位 90%复极(MAPD)(MAPD 比野生型(47.4 ± 2.6 ms 比 55.5 ± 2.4 ms,n = 10,P < 0.05),更容易诱发室性心律失常(70%(7/10)比 10%(1/10),P < 0.05),同时伴有儿茶酚胺浓度升高(肾上腺素:1.75 ± 0.18 nmol/L 比 0.68 ± 0.10 nmol/L n = 10,P < 0.05;去甲肾上腺素:9.56 ± 0.71 nmol/L 比 2.52 ± 0.31 nmol/L n = 10,P < 0.05)。当用β-肾上腺素能受体拮抗剂美托洛尔灌注时,AMPKα2 的 MAPD 缩短和室性心律失常易感性增加几乎可以被消除。这表明,儿茶酚胺释放引起的β-肾上腺素能受体激活主要负责与 AMPKα2 相关的电生理学变化。这具有重要的临床意义,因为在 AMP 激活的蛋白激酶-α2 基因有问题的患者中,我们可能会在未来使用β-肾上腺素能受体拮抗剂来预防心律失常。

影响声明据我们所知,这是首次探索 AMP 激活的蛋白激酶-α2(AMPKα2)对心脏电生理学的作用,我们发现,儿茶酚胺释放引起的β-肾上腺素能受体激活主要负责与 AMPKα2 缺失相关的电生理学变化。这具有重要的临床意义,因为在 AMPKα2 基因有问题的患者中,我们可能会在未来使用β-肾上腺素能受体拮抗剂来预防心律失常。

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