Fibroblasts in heart scar tissue directly regulate cardiac excitability and arrhythmogenesis

• 成果类型: Article
• 署名作者: Wang, Yijie; Li, Qihao; Tao, Bo; Angelini, Marina; Ramadoss, Sivakumar; Sun, Baiming; Wang, Ping; Krokhaleva, Yuliya; Ma, Feiyang; Gu, Yiqian; Espinoza, Alejandro; Yamauchi, Ken; Pellegrini, Matteo; Novitch, Bennett; Olcese, Riccardo; Qu, Zhilin; Song, Zhen; Deb, Arjun
• 署名单位: University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; Peng Cheng Laboratory; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; Northwestern University; Feinberg School of Medicine; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9025
• DOI: 10.1126/science.adh9925
• 发表日期: 2023-09-29
• 页码: 1480-1487
• 关键词: mechanically induced potentials; atrial fibroblasts; sodium-channels; connexin43; repair; MODEL; conductance; activation; mechanisms; expression

摘要

After heart injury, dead heart muscle is replaced by scar tissue. Fibroblasts can electrically couple with myocytes, and changes in fibroblast membrane potential can lead to myocyte excitability, which suggests that fibroblast-myocyte coupling in scar tissue may be responsible for arrhythmogenesis. However, the physiologic relevance of electrical coupling of myocytes and fibroblasts and its impact on cardiac excitability in vivo have never been demonstrated. We genetically engineered a mouse that expresses the optogenetic cationic channel ChR2 (H134R) exclusively in cardiac fibroblasts. After myocardial infarction, optical stimulation of scar tissue elicited organ-wide cardiac excitation and induced arrhythmias in these animals. Complementing computational modeling with experimental approaches, we showed that gap junctional and ephaptic coupling, in a synergistic yet functionally redundant manner, excited myocytes coupled to fibroblasts.