背景:心房中微生物群衍生的三甲胺N-氧化物(TMAO)的积累与房性心律失常的发展和进展有关。丁酸,一种主要的短链脂肪酸,在维持肠道稳态和缓解全身炎症中起着至关重要的作用,这可能会减少房性心律失常的发生。
目的:本研究探讨丁酸在调节TMAO介导的心房重构和心律失常中的作用。
方法:全细胞膜片钳实验,西方印迹,和免疫细胞化学用于分析电活动和信号,分别,在有或没有丁酸钠(SB)给药的TMAO处理的HL-1心房肌细胞中。采用遥测心电图记录和超声心动图、Masson三色染色和免疫组织化学检查心房功能和组织病理学,分别,在有和没有SB给药的TMAO治疗的小鼠中。
结果:与对照细胞相比,TMAO处理的HL-1心肌细胞表现出减少的动作电位持续时间(APD),肌浆网(SR)钙含量升高,较大的L型钙电流(ICa-L),增加Na+/Ca2+交换剂(NCX)电流,并增加钾电流。然而,SB和TMAO的组合产生了类似的APD,SR钙含量,ICa-L,瞬态外向钾电流(Ito),与对照相比,超快延迟整流钾电流(IKur)。此外,TMAO处理的HL-1肌细胞显示内质网(ER)应激信号激活增加,随着PKR样内质网应激激酶(PERK)/IRE1α轴的激活和磷酸化IP3R的表达增加,NCX,和Kv1.5,与对照或用TMAO和SB的组合处理的HL-1细胞相比。TMAO治疗的小鼠表现出心房异位搏动,心房功能受损,心房纤维化增加,与对照组和TMAO联合SB治疗的小鼠相比,PERK/IRE1α轴激活对ER应激信号的激活更大。
结论:TMAO给药导致PERK/IRE1α轴激活,这可能会增加心房重构和心律失常发生。SB治疗减轻了TMAO引起的ER应激。这一发现表明SB给药是治疗TMAO诱发的房性心律失常的有价值的策略。
BACKGROUND: The accumulation of microbiota-derived trimethylamine N-oxide (TMAO) in the atrium is linked to the development and progression of atrial arrhythmia. Butyrate, a major short-chain fatty acid, plays a crucial role in sustaining intestinal homeostasis and alleviating systemic inflammation, which may reduce atrial arrhythmogenesis.
OBJECTIVE: This study explored the roles of butyrate in regulating TMAO-mediated atrial remodeling and arrhythmia.
METHODS: Whole-cell patch clamp experiments, Western blotting, and immunocytochemistry were used to analyze electrical activity and signaling, respectively, in TMAO-treated HL-1 atrial myocytes with or without sodium butyrate (SB) administration. Telemetry electrocardiographic recording and echocardiography and Masson\'s trichrome staining and immunohistochemistry were employed to examine atrial function and histopathology, respectively, in mice treated with TMAO with and without SB administration.
RESULTS: Compared with control cells, TMAO-treated HL-1 myocytes exhibited reduced action potential duration (APD), elevated sarcoplasmic reticulum (SR) calcium content, larger L-type calcium current (ICa-L), increased Na+/Ca2+ exchanger (NCX) current, and increased potassium current. However, the combination of SB and TMAO resulted in similar APD, SR calcium content, ICa-L, transient outward potassium current (Ito), and ultrarapid delayed rectifier potassium current (IKur) compared with controls. Additionally, TMAO-treated HL-1 myocytes exhibited increased activation of endoplasmic reticulum (ER) stress signaling, along with increased PKR-like ER stress kinase (PERK)/IRE1α axis activation and expression of phospho-IP3R, NCX, and Kv1.5, compared with controls or HL-1 cells treated with the combination of TMAO and SB. TMAO-treated mice exhibited atrial ectopic beats, impaired atrial function, increased atrial fibrosis, and greater activation of ER stress signaling with PERK/IRE1α axis activation compared with controls and mice treated with TMAO combined with SB.
CONCLUSIONS: TMAO administration led to PERK/IRE1α axis activation, which may increase atrial remodeling and arrhythmogenesis. SB treatment mitigated TMAO-elicited ER stress. This finding suggests that SB administration is a valuable strategy for treating TMAO-induced atrial arrhythmia.