State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Beihua South Road, JingHai District, Tianjin 301617, China.
Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China.
Theranostics. 2024 Oct 7;14(17):6625-6651. doi: 10.7150/thno.99065. eCollection 2024.
Stroke-related cardiovascular diseases have attracted considerable attention, with atrial fibrillation (AF) being among the most frequent complications. Despite increasing clinical evidence, experimental models of stroke-induced AF are still lacking, hindering mechanistic discoveries and the development of adequate therapeutics targeting this stroke-heart syndrome (SHS). This study aims to create a rat model of ischemic stroke-induced AF (ISIAF) and to explore the efficacy and mechanism of Wenxin Keli (WK), an antiarrhythmic Chinese medicine. The middle cerebral artery occlusion/reperfusion model was adapted to create subacute brain ischemia in rats with normal cardiac function. Invasive electrophysiologic studies and optical mapping were performed to evaluate the altered electrophysiological parameters and Ca handling properties. RNA-seq analysis, RT-PCR, and immunohistochemistry (IHC) with immunofluorescence (IF) were employed to assess the SHS model and elucidate the mechanisms of ISIAF and the effects of WK. UPLC/Q-TOF-MS, molecular docking, and whole-cell patch recordings were used to identify the active components of WK for SHS. Ischemic stroke aggravated atrial electrical instability, altered action potential duration (APD), Ca transient duration (CaT), conduction heterogeneity, and spatially discordant alternans in SHS rat hearts. These abnormalities were alleviated by WK. RNA-seq analysis revealed that M-mediated cholinergic synapse signaling and L-type calcium channel (LTCCs)-mediated Ca signaling play prominent roles in ISIAF development and its reversal by WK. UPLC/Q-TOF-MS analysis identified 19 WK components as the main components in plasma after WK treatment. Molecular docking screening identified Dioscin as the major active component of WK. WK and Dioscin reduced I in a concentration-dependent manner with a half-maximal inhibitory concentration of 24.254 ± 2.051 mg/mL and 8.666 ± 0.777 µmol/L, respectively. This study established an experimental model of ISIAF capable of characterizing clinically relevant atrial electrophysiological changes post-cerebral ischemia. Molecular mechanistic studies revealed that the cholinergic-calcium signaling pathway is central to this brain-heart syndrome. Ischemic stroke-induced atrial fibrillation is partially reversible by the Chinese medicine Wenxin Keli, which acts via regulation of the cholinergic-calcium signaling pathway, with its active component Dioscin directly binding to I and inhibiting I.
中风相关的心血管疾病引起了广泛关注，其中心房颤动（AF）是最常见的并发症之一。尽管临床证据不断增加，但中风诱导的 AF 的实验模型仍然缺乏，这阻碍了对这种中风-心脏综合征（SHS）的机制发现和足够治疗方法的开发。本研究旨在建立一种大鼠缺血性中风诱导的 AF（ISIAF）模型，并探讨稳心颗粒（WK），一种抗心律失常的中药的疗效和机制。采用大脑中动脉闭塞/再灌注模型，在心脏功能正常的大鼠中建立亚急性脑缺血。通过侵入性电生理研究和光学映射来评估电生理参数和 Ca 处理特性的改变。采用 RNA-seq 分析、RT-PCR 和免疫组织化学（IHC）与免疫荧光（IF）评估 SHS 模型，并阐明 ISIAF 的机制和 WK 的作用。UPLC/Q-TOF-MS、分子对接和全细胞膜片钳记录用于鉴定 WK 治疗 SHS 的活性成分。缺血性中风加重了心房电不稳定性，改变了动作电位时程（APD）、钙瞬变时程（CaT）、传导异质性和 SHS 大鼠心脏中空间不一致的交替。WK 减轻了这些异常。RNA-seq 分析表明，M 介导的胆碱能突触信号和 L 型钙通道（LTCCs）介导的 Ca 信号在 ISIAF 的发展及其被 WK 逆转中起重要作用。UPLC/Q-TOF-MS 分析鉴定出 19 种 WK 成分作为 WK 治疗后血浆中的主要成分。分子对接筛选发现薯蓣皂苷元是 WK 的主要活性成分。WK 和薯蓣皂苷元以浓度依赖性方式降低 I，半数最大抑制浓度分别为 24.254±2.051mg/mL 和 8.666±0.777µmol/L。本研究建立了一种能够描述脑缺血后临床相关心房电生理变化的 ISIAF 实验模型。分子机制研究表明，胆碱能-钙信号通路是这种脑-心综合征的核心。中药稳心颗粒部分逆转缺血性中风诱导的心房颤动，其作用机制是通过调节胆碱能-钙信号通路，其活性成分薯蓣皂苷元直接与 I 结合并抑制 I。
