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

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) (MAPD90) 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 MAPD90 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.