Olgar Yusuf, Durak Ayşegül, Turan Belma
Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Türkiye.
Department of Biophysics, Faculty of Medicine, Lokman Hekim University, Ankara, Türkiye.
Anatol J Cardiol. 2024 Dec 10;29(2):83-94. doi: 10.14744/AnatolJCardiol.2024.4719.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are known for their benefits in conditions like cardiovascular diseases in type 2 diabetes and obesity. They also show promise for aging-related conditions with minimal side effects. However, their impact on cardiovascular risk is still debated. Notably, some long-acting GLP-1RAs cause a sustained increase in heart rate on the first day of use without a clear mechanism. To understand their short-term effects, we examined acute GLP-1R agonism on the electrical activity of elderly hearts.
In this study, we utilized in vivo electrocardiography, in vitro cellular electrophysiology experiments, and biochemical measurements on heart preparations from 6-month-old (Adult) and 24-month-old (aged) BALB/c mice.
A single liraglutide injection (0.3 mg/kg) induced repetitive, self-sustained arrhythmogenic electrocardiograms in aged mice (24 months old) but had no effect on adults (6 months old) within the first 10 minutes. Acute application of liraglutide to isolated ventricular cardiomyocytes from aged mice significantly prolonged the late phase of action potential repolarization (APR90). This was due to suppressed K+ currents and increased persistent Na+currents (Late-INa), primarily through delayed recovery from inactivation of Na+ currents. Additionally, liraglutide increased Ca2+ spark frequency and wave formation by enhancing Ca2+ release from the sarcoplasmic reticulum, affecting both Na+ and Ca2+ regulation in aging cells. Liraglutide also induced casein kinase 2 (CK2) hyperphosphorylation in aged cardiomyocytes, which a CK2 inhibitor could reverse, normalizing APR90 by reducing Late-INa and enhancing K+ currents.
These findings reveal that acute GLP-1R agonism can disrupt electrical signaling and induce arrhythmia in aged mice through CK2 hyperphosphorylation, providing new insights into the cardiovascular effects of GLP-1RAs in the elderly.
胰高血糖素样肽-1受体激动剂（GLP-1RAs）因其在2型糖尿病和肥胖症等心血管疾病中的益处而闻名。它们在与衰老相关的疾病中也显示出前景，且副作用极小。然而，它们对心血管风险的影响仍存在争议。值得注意的是，一些长效GLP-1RAs在使用第一天会导致心率持续增加，但其机制尚不清楚。为了解它们的短期影响，我们研究了急性GLP-1R激动对老年心脏电活动的作用。
在本研究中，我们对6个月大（成年）和24个月大（老年）的BALB/c小鼠的心脏标本进行了体内心电图检查、体外细胞电生理实验和生化测量。
单次注射利拉鲁肽（0.3 mg/kg）在老年小鼠（24个月大）中诱发了重复性、自我维持的致心律失常心电图，但在最初10分钟内对成年小鼠（6个月大）没有影响。将利拉鲁肽急性应用于老年小鼠分离的心室心肌细胞，可显著延长动作电位复极化的晚期阶段（APR90）。这是由于K+电流受到抑制，持续性Na+电流（Late-INa）增加，主要是通过Na+电流失活后的恢复延迟所致。此外，利拉鲁肽通过增强肌浆网的Ca2+释放增加了Ca2+火花频率和波的形成，影响了衰老细胞中的Na+和Ca2+调节。利拉鲁肽还诱导老年心肌细胞中的酪蛋白激酶2（CK2）过度磷酸化，CK2抑制剂可以逆转这种情况，通过减少Late-INa和增强K+电流使APR90恢复正常。
这些发现表明，急性GLP-1R激动可通过CK2过度磷酸化破坏老年小鼠的电信号传导并诱发心律失常，为GLP-1RAs在老年人中的心血管效应提供了新的见解。
