KCa3.1 Promotes Proinflammatory Exosome Secretion by Activating AKT/Rab27a in Atrial Myocytes during Rapid Pacing.

IF 3.4 4区医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS

Cardiovascular Therapeutics Pub Date : 2023-01-01 DOI:10.1155/2023/3939360

Dishiwen Liu, Huiyu Chen, Yuntao Fu, Yajun Yao, Shanqing He, Youcheng Wang, Zhen Cao, Xuewen Wang, Mei Yang, Qingyan Zhao

{"title":"KCa3.1 Promotes Proinflammatory Exosome Secretion by Activating AKT/Rab27a in Atrial Myocytes during Rapid Pacing.","authors":"Dishiwen Liu, Huiyu Chen, Yuntao Fu, Yajun Yao, Shanqing He, Youcheng Wang, Zhen Cao, Xuewen Wang, Mei Yang, Qingyan Zhao","doi":"10.1155/2023/3939360","DOIUrl":null,"url":null,"abstract":"Purpose: The aim of this study was to investigate the role of the medium-conductance calcium-activated potassium channel (KCNN4, KCa3.1) in the secretion of proinflammatory exosomes by atrial myocytes.Methods: Eighteen beagles were randomly divided into the sham group (n = 6), pacing group (n = 6), and pacing+TRAM-34 group (n = 6). Electrophysiological data, such as the effective refractory period, atrial fibrillation (AF) induction, and AF duration, were collected by programmed stimulation. Atrial tissues were subjected to hematoxylin and eosin, Masson's trichrome, and immunofluorescence staining. The expression of KCa3.1 and Rab27a was assessed by immunohistochemistry and western blotting. The downstream signaling pathways involved in KCa3.1 were examined by rapid pacing or overexpressing KCNN4 in HL-1 cells.Results: Atrial rapid pacing significantly induced electrical remodeling, inflammation, fibrosis, and exosome secretion in the canine atrium, while TRAM-34 (KCa3.1 blocker) inhibited these changes. Compared with those in control HL-1 cells, the levels of exosome markers and inflammatory factors were increased in pacing HL-1 cells. Furthermore, the levels of CD68 and iNOS in macrophages incubated with exosomes derived from HL-1 cells were higher in the pacing-exo group than in the control group. More importantly, KCa3.1 regulated exosome secretion through the AKT/Rab27a signaling pathway. Similarly, inhibiting the downstream signaling pathway of KCa3.1 significantly inhibited exosome secretion.Conclusions: KCa3.1 promotes proinflammatory exosome secretion through the AKT/Rab27a signaling pathway. Inhibiting the KCa3.1/AKT/Rab27a signaling pathway reduces myocardial tissue structural remodeling in AF.","PeriodicalId":9582,"journal":{"name":"Cardiovascular Therapeutics","volume":"2023 ","pages":"3939360"},"PeriodicalIF":3.4000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10079387/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cardiovascular Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1155/2023/3939360","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}

引用次数: 0

Abstract

Purpose: The aim of this study was to investigate the role of the medium-conductance calcium-activated potassium channel (KCNN4, KCa3.1) in the secretion of proinflammatory exosomes by atrial myocytes.

Methods: Eighteen beagles were randomly divided into the sham group (n = 6), pacing group (n = 6), and pacing+TRAM-34 group (n = 6). Electrophysiological data, such as the effective refractory period, atrial fibrillation (AF) induction, and AF duration, were collected by programmed stimulation. Atrial tissues were subjected to hematoxylin and eosin, Masson's trichrome, and immunofluorescence staining. The expression of KCa3.1 and Rab27a was assessed by immunohistochemistry and western blotting. The downstream signaling pathways involved in KCa3.1 were examined by rapid pacing or overexpressing KCNN4 in HL-1 cells.

Results: Atrial rapid pacing significantly induced electrical remodeling, inflammation, fibrosis, and exosome secretion in the canine atrium, while TRAM-34 (KCa3.1 blocker) inhibited these changes. Compared with those in control HL-1 cells, the levels of exosome markers and inflammatory factors were increased in pacing HL-1 cells. Furthermore, the levels of CD68 and iNOS in macrophages incubated with exosomes derived from HL-1 cells were higher in the pacing-exo group than in the control group. More importantly, KCa3.1 regulated exosome secretion through the AKT/Rab27a signaling pathway. Similarly, inhibiting the downstream signaling pathway of KCa3.1 significantly inhibited exosome secretion.

Conclusions: KCa3.1 promotes proinflammatory exosome secretion through the AKT/Rab27a signaling pathway. Inhibiting the KCa3.1/AKT/Rab27a signaling pathway reduces myocardial tissue structural remodeling in AF.

查看原文本刊更多论文

KCa3.1通过激活心房肌细胞AKT/Rab27a促进促炎外泌体分泌。

目的:本研究旨在探讨中导钙活化钾通道(KCNN4, KCa3.1)在心房肌细胞促炎外泌体分泌中的作用。方法:将18只beagle随机分为假手术组(n = 6)、起搏组(n = 6)和起搏+TRAM-34组(n = 6)，采用程序化刺激法收集有效不应期、心房颤动诱导、房颤持续时间等电生理数据。心房组织进行苏木精、伊红、马松三色和免疫荧光染色。免疫组织化学和western blotting检测KCa3.1和Rab27a的表达。在HL-1细胞中通过快速起搏或过表达KCNN4来检测KCa3.1参与的下游信号通路。结果:心房快速起搏显著诱导犬心房电重构、炎症、纤维化和外泌体分泌，而TRAM-34 (KCa3.1阻滞剂)抑制这些变化。与对照HL-1细胞相比，起搏HL-1细胞外泌体标志物和炎症因子水平升高。此外，与HL-1细胞衍生的外泌体孵育的巨噬细胞中，pace -exo组的CD68和iNOS水平高于对照组。更重要的是，KCa3.1通过AKT/Rab27a信号通路调节外泌体分泌。同样，抑制KCa3.1的下游信号通路可显著抑制外泌体的分泌。结论:KCa3.1通过AKT/Rab27a信号通路促进促炎外泌体分泌。抑制KCa3.1/AKT/Rab27a信号通路可减少房颤心肌组织结构重构。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cardiovascular Therapeutics 医学-心血管系统

CiteScore

5.60

自引率

0.00%

发文量

审稿时长

6 months

期刊介绍： Cardiovascular Therapeutics (formerly Cardiovascular Drug Reviews) is a peer-reviewed, Open Access journal that publishes original research and review articles focusing on cardiovascular and clinical pharmacology, as well as clinical trials of new cardiovascular therapies. Articles on translational research, pharmacogenomics and personalized medicine, device, gene and cell therapies, and pharmacoepidemiology are also encouraged. Subject areas include (but are by no means limited to): Acute coronary syndrome Arrhythmias Atherosclerosis Basic cardiac electrophysiology Cardiac catheterization Cardiac remodeling Coagulation and thrombosis Diabetic cardiovascular disease Heart failure (systolic HF, HFrEF, diastolic HF, HFpEF) Hyperlipidemia Hypertension Ischemic heart disease Vascular biology Ventricular assist devices Molecular cardio-biology Myocardial regeneration Lipoprotein metabolism Radial artery access Percutaneous coronary intervention Transcatheter aortic and mitral valve replacement.