Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China; Department of Ophthalmology, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, 150081, China.
Department of General Practice, The Forth Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, 150081, China.
Biochem Biophys Res Commun. 2019 Sep 17;517(2):272-277. doi: 10.1016/j.bbrc.2019.07.041. Epub 2019 Jul 23.
QT interval prolongation and depolarization of resting membrane potential (RMP) were found in acute myocardial infarction (MI) which is involved in the arrhythmogenic mechanism and raising the risk to initiate torsade de pointes. However, clinical anti-arrhythmic agents that primarily act on QT interval and RMP are not currently available. Our objective was to determine whether Apelin, an endogenous peptide ligand of receptor APJ, affects QT interval and RMP and underlying mechanisms. To test this viewpoint, mice were subjected to MI by ligating the left main coronary artery and Apelin was applied through tail vein at 5 min prior coronary occlusion in tested group. Compared to MI group, pretreatment of Apelin (15 μg/kg) shortened QTc and QT interval induced by MI, significantly elevated RMP and shortened action potential duration (APD) by increased I currents recorded using whole-cell patch technique from cardiomyocytes underwent MI. In cultured neonatal mouse cardiomyocytes, Apelin (1 μmol/L) restored hypoxia-induced Kir2.1 down-regulation, which was abolished by IP3K inhibitor LY-294002. Additionally, Apelin elicited a time-dependent increase in phosphorylation of Akt leading to increase in PI3-kinase activity. These results showed that Apelin enhanced I/Kir2.1 currents via IP3K pathway as by rescue ischemia- and hypoxia-induced RMP depolarization and prolongation of QT interval, which may prevent or cure acute ischemic-mediated arrhythmias. This study brings new information to anti-arrhythmic theories and provides a potential target for the clinical management of acute ischemia-related arrhythmias.
在急性心肌梗死（MI）中发现 QT 间期延长和静息膜电位（RMP）去极化，这与心律失常机制有关，并增加引发尖端扭转型室性心动过速的风险。然而，目前尚无专门作用于 QT 间期和 RMP 的临床抗心律失常药物。我们的目的是确定内源性肽配体受体 APJ 的 Apelin 是否会影响 QT 间期和 RMP 以及潜在机制。为了验证这一观点，通过结扎左冠状动脉主干将小鼠诱导成 MI，并用尾静脉在冠状动脉闭塞前 5 分钟给予 Apelin。与 MI 组相比，Apelin（15μg/kg）预处理可缩短由 MI 诱导的 QTc 和 QT 间期，显著升高 RMP，并通过增加全细胞膜片钳技术从经历 MI 的心肌细胞中记录的 I 电流缩短动作电位时程（APD）。在培养的新生小鼠心肌细胞中，Apelin（1μmol/L）恢复了缺氧诱导的 Kir2.1 下调，而 IP3K 抑制剂 LY-294002 则消除了这种下调。此外，Apelin 引起 Akt 磷酸化的时间依赖性增加，导致 PI3-激酶活性增加。这些结果表明，Apelin 通过 IP3K 途径增强 I/Kir2.1 电流，从而挽救缺血和缺氧引起的 RMP 去极化和 QT 间期延长，这可能预防或治疗急性缺血性介导的心律失常。这项研究为抗心律失常理论提供了新信息，并为急性缺血相关心律失常的临床治疗提供了潜在靶点。
