The Reversal Effect of Sigma-1 Receptor (S1R) Agonist, SA4503, on Atrial Fibrillation After Depression and Its Underlying Mechanism
The Reversal Effect of Sigma-1 Receptor (S1R) Agonist, SA4503, on Atrial Fibrillation After Depression and Its Underlying Mechanism
复制标题
Sigma-1 受体 (S1R) 激动剂 SA4503 对抑郁后心房颤动的逆转作用及其潜在机制。
DOI：
10.3389/fphys.2019.01346
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发表时间：
2019-11-14
影响因子：
4
通讯作者：
Yang, Bo
中科院分区：
文献类型：
--
作者：
Liu, Xin;Qu, Chuan;Yang, Bo
目的 Sigma-1 受体已被研究并显示在抑郁症和心血管疾病中发挥保护作用。 SA4503 被称为 sigma 1 受体激动剂，在抑郁症大鼠模型中调节心脏钙和钾通道。然而，SA4503是否可以减轻慢性轻度应激后的心肌炎症或心房传导连接仍不清楚。方法和结果 Sprague-Dawley 雄性大鼠接受 SA4503 28 天治疗，同时进行慢性轻度应激。每日剂量后评估行为测量。此外，还进行了多电极阵列评估、电生理学研究、免疫组织化学分析、组织学分析和蛋白质印迹分析。抑郁症大鼠的心脏表现出异常的电活动，包括兴奋传播紊乱和总激活时间（TAT）延长。此外，与对照组相比，抑郁组由突发刺激引起的房性心律失常（AA）发生率更高，持续时间更长。这些变化与传导结点的减少和空间异质性的增强有关。重要的是，抑郁的大鼠心脏显示出更多的炎症因子（TGF-α、IL-6 和 TGF-β）表达、更多的胶原蛋白在细胞外基质中分布以及间隙连接蛋白（CX40 和 CX43）的表达降低。此外，SA4503 部分减轻了抑郁症组的上述指标（所有组 P < 0.01）。结论 这些发现显示了 sigma 1R 激动剂 SA4503 的作用；它可以减轻慢性轻度应激后心房心肌炎症和传导连接。 SA4503可能是通过增加传导功能、改善连接蛋白40和43的表达以及减少心肌炎症来治疗抑郁相关AA的有前途的药物。
Aim Sigma-1 receptors have been investigated and shown to play a protective role in both depression and cardiovascular disease. SA4503, known as a sigma 1 receptor agonist, regulates cardiac calcium and potassium channels in rat models of depression. However, it remains unknown whether SA4503 can alleviate myocardial inflammation or conduction junctions in the atrium after exposure to chronic mild stress. Methods and Results Sprague-Dawley male rats received 28-day treatment with SA4503, simultaneously with chronic mild stress. Behavior measurements were assessed after the daily doses. Additionally, a multielectrode array assessment, electrophysiological study, immunohistochemistry analysis, histological analysis, and Western blot analysis were performed. Depression rats' hearts showed abnormal electrical activity, including disordered excitation propagation and prolonged total activation time (TAT). In addition, atrial arrhythmias (AAs), induced by burst stimulation, showed higher incidence and longer duration in the depression group compared to the control group. These changes were related to reduced conduction junctions and enhanced spatial heterogeneity. Importantly, depressed rat hearts showed greater expression of inflammatory factors (TGF-alpha, IL-6, and TGF-beta), more collagen distribution in the extracellular matrix, and lower expression of gap junction proteins (CX40 and CX43). Furthermore, SA4503 partially mitigated the above indices in the depression group (P < 0.01 for all groups). Conclusion These findings show the effects of the sigma 1R agonist SA4503; it alleviates atrial myocardial inflammation and conduction junctions after chronic mild stress. SA4503 may be the promising pharmacological agent to treat depression-related AAs by increasing conduction function, improving the expression of connexin 40 and 43, and reducing cardiac myocardial inflammation.