Altieri Danielle I, Etzion Yoram, Anderson Hope D
College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
Canadian Centre for Agri-Food Research in Health and Medicine (CCARM), Albrechtsen Research Centre, St Boniface Hospital, Winnipeg, MB, Canada.
Front Pharmacol. 2023 Apr 11;14:1142583. doi: 10.3389/fphar.2023.1142583. eCollection 2023.
Pathological remodeling of atrial tissue renders the atria more prone to arrhythmia upon arrival of electrical triggers. Activation of the renin-angiotensin system is an important factor that contributes to atrial remodeling, which may result in atrial hypertrophy and prolongation of P-wave duration. In addition, atrial cardiomyocytes are electrically coupled gap junctions, and electrical remodeling of connexins may result in dysfunction of coordinated wave propagation within the atria. Currently, there is a lack of effective therapeutic strategies that target atrial remodeling. We previously proposed that cannabinoid receptors (CBR) may have cardioprotective qualities. CB13 is a dual cannabinoid receptor agonist that activates AMPK signaling in ventricular cardiomyocytes. We reported that CB13 attenuates tachypacing-induced shortening of atrial refractoriness and inhibition of AMPK signaling in the rat atria. Here, we evaluated the effects of CB13 on neonatal atrial rat cardiomyocytes (NRAM) stimulated by angiotensin II (AngII) in terms of atrial myocyte enlargement and mitochondrial function. CB13 inhibited AngII-induced enhancement of atrial myocyte surface area in an AMPK-dependent manner. CB13 also inhibited mitochondrial membrane potential deterioration in the same context. However, AngII and CB13 did not affect mitochondrial permeability transition pore opening. We further demonstrate that CB13 increased Cx43 compared to AngII-treated neonatal rat atrial myocytes. Overall, our results support the notion that CBR activation promotes atrial AMPK activation, and prevents myocyte enlargement (an indicator that suggests pathological hypertrophy), mitochondrial depolarization and Cx43 destabilization. Therefore, peripheral CBR activation should be further tested as a novel treatment strategy in the context of atrial remodeling.
心房组织的病理性重塑使心房在电触发因素出现时更容易发生心律失常。肾素 - 血管紧张素系统的激活是导致心房重塑的一个重要因素，这可能会导致心房肥大和P波持续时间延长。此外，心房心肌细胞通过缝隙连接进行电耦合，连接蛋白的电重塑可能导致心房内协调波传播功能障碍。目前，缺乏针对心房重塑的有效治疗策略。我们之前提出大麻素受体（CBR）可能具有心脏保护作用。CB13是一种双大麻素受体激动剂，可激活心室心肌细胞中的AMPK信号通路。我们报道CB13可减轻快速起搏诱导的大鼠心房不应期缩短以及AMPK信号通路的抑制。在此，我们从心房肌细胞增大和线粒体功能方面评估了CB13对血管紧张素II（AngII）刺激的新生大鼠心房心肌细胞（NRAM）的影响。CB13以AMPK依赖的方式抑制AngII诱导的心房肌细胞表面积增加。在相同情况下，CB13还抑制线粒体膜电位的恶化。然而，AngII和CB13并不影响线粒体通透性转换孔的开放。我们进一步证明，与AngII处理的新生大鼠心房肌细胞相比，CB13增加了Cx43的表达。总体而言，我们的结果支持以下观点：CBR激活可促进心房AMPK激活，并防止肌细胞增大（提示病理性肥大的指标）、线粒体去极化和Cx43不稳定。因此，在心房重塑的背景下，应进一步测试外周CBR激活作为一种新型治疗策略的效果。
