参松养心通过抑制亚铁转运蛋白介导的细胞内铁过载来减轻代谢综合征诱导的心房颤动。
Shensong Yangxin attenuates metabolic syndrome-induced atrial fibrillation via inhibition of ferroportin-mediated intracellular iron overload.
机构信息
Department of Cardiology, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, No.238 Jiefang Road, Wuchang, Wuhan 430060, China; Hubei Key Laboratory of Cardiology, No.238 Jiefang Road, Wuchang, Wuhan 430060, China.
Department of Cardiology, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, No.238 Jiefang Road, Wuchang, Wuhan 430060, China; Hubei Key Laboratory of Cardiology, No.238 Jiefang Road, Wuchang, Wuhan 430060, China.
出版信息
Phytomedicine. 2022 Jul;101:154086. doi: 10.1016/j.phymed.2022.154086. Epub 2022 Apr 5.
BACKGROUND
Shensong Yangxin (SSYX) is a traditional Chinese medicine been widely used clinically to treat various arrhythmias including atrial fibrillation (AF). However, the role and precise mechanism of SSYX in MS-induced AF have not yet been elucidated.
PURPOSE
To elucidate the protective effects of SSYX on MS-induced AF and its possible mechanisms of action.
METHODS
Male Wistar rats (180-220 g) were fed a 16-week high-carbohydrate, high-fat (HCHF) diet together with 25% fructose in drinking water to produce a MS model. Low-concentration (SSYX-L, 0.4 g/kg) and high-concentration (SSYX-H, 0.8 g/kg) of SSYX were given by daily gavage 8-weeks following HCHF diet for 8-weeks. In vivo electrophysiological study, histological analysis, RNA-sequence (RNA-Seq) and gene ontology (GO) analysis, qRT-PCR and western blot were performed.
RESULTS
Both low-concentration and high-concentration of SSYX could inhibit MS-induced AF susceptibility, electrical remodeling and structural remodeling. Results from RNA-sequence analysis revealed intracellular iron homeostasis mediated the protective effect of SSYX against MS. In vivo and in vitro experiments both demonstrated that SSYX up-regulated ferroportin (Fpn) expression and ameliorated intracellular iron overload induced by MS. To verified whether Fpn is the target of SSYX and intracellular iron overload mediated the protective effect of SSYX against MS, adeno-associated virus type 9 (AAV9) delivery system was used. Knocking down Fpn (AAV9-shFpn) markedly aggravated the reactive oxygen species (ROS) production, electrical remodeling and atrial fibrosis induced by MS, leading to a further increase of AF susceptibility induced by MS.
CONCLUSION
Our study demonstrated for the first time that SSYX reduced AF susceptibility, inhibited electrical remodeling and structural remodeling via up-regulating Fpn, decreasing intracellular iron overload and reducing ROS production. These results suggest that SSYX might be a potential therapeutic agent for the treatment of MS-induced AF.
背景
参松养心（SSYX）是一种传统中药，临床上广泛用于治疗各种心律失常，包括心房颤动（AF）。然而，SSYX 在 MS 诱导的 AF 中的作用及其确切机制尚不清楚。
目的
阐明 SSYX 对 MS 诱导的 AF 的保护作用及其可能的作用机制。
方法
雄性 Wistar 大鼠（180-220g）给予 16 周高碳水化合物、高脂肪（HCHF）饮食，并在饮用水中加入 25%果糖，以产生 MS 模型。在 HCHF 饮食 8 周后，给予低浓度（SSYX-L，0.4g/kg）和高浓度（SSYX-H，0.8g/kg）的 SSYX 每日灌胃 8 周。进行体内电生理研究、组织学分析、RNA 测序（RNA-Seq）和基因本体（GO）分析、qRT-PCR 和 Western blot。
结果
低浓度和高浓度的 SSYX 均可抑制 MS 诱导的 AF 易感性、电重构和结构重构。RNA 测序分析结果表明，细胞内铁稳态介导了 SSYX 对 MS 的保护作用。体内和体外实验均表明，SSYX 上调铁蛋白（Fpn）表达，改善 MS 引起的细胞内铁过载。为了验证 Fpn 是否是 SSYX 的靶点以及细胞内铁过载是否介导了 SSYX 对 MS 的保护作用，使用腺相关病毒 9（AAV9）传递系统。敲低 Fpn（AAV9-shFpn）显著加重 MS 引起的活性氧（ROS）产生、电重构和心房纤维化，导致 MS 诱导的 AF 易感性进一步增加。
结论
本研究首次表明，SSYX 通过上调 Fpn、减少细胞内铁过载和减少 ROS 产生，降低 AF 易感性，抑制电重构和结构重构。这些结果表明，SSYX 可能是治疗 MS 诱导的 AF 的潜在治疗剂。
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