Department of Cardiology, The General Hospital of Western Theater Command (Chengdu Military General Hospital), Chengdu 610083, China.
Department of Toxicology, The Ministry of Education Key Laboratory of Hazard Assessment and Control in Special Operational Environment, Shaanxi Key Laboratory of Free Radical Biology and Medicine, School of Public Health, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
Oxid Med Cell Longev. 2019 May 14;2019:6408352. doi: 10.1155/2019/6408352. eCollection 2019.
Cardiac fibroblasts (CFs) are a critical cell population responsible for myocardial extracellular matrix homeostasis. After stimulation by myocardial infarction (MI), CFs transdifferentiate into cardiac myofibroblasts (CMFs) and play a fundamental role in the fibrotic healing response. Transient receptor potential ankyrin 1 (TRPA1) channels are cationic ion channels with a high fractional Ca current, and they are known to influence cardiac function after MI injury; however, the molecular mechanisms regulating CMF transdifferentiation remain poorly understood. TRPA1 knockout mice, their wild-type littermates, and mice pretreated with the TRPA1 agonist cinnamaldehyde (CA) were subjected to MI injury and monitored for survival, cardiac function, and fibrotic remodeling. TRPA1 can drive myofibroblast transdifferentiation initiated 1 week after MI injury. In addition, we explored the underlying mechanisms via experiments through gene transfection alone or in combination with inhibitor treatment. TRPA1 overexpression fully activated CMF transformation, while CFs lacking TRPA1 were refractory to transforming growth factor - (TGF--) induced transdifferentiation. TGF- enhanced TRPA1 expression, which promoted the Ca-responsive activation of calcineurin (CaN). Moreover, dual-specificity tyrosine-regulated kinase-1a (DYRK1A) regulated CaN-mediated NFAT nuclear translocation and TRPA1-dependent transdifferentiation. These findings suggest a potential therapeutic role for TRPA1 in the regulation of CMF transdifferentiation in response to MI injury and indicate a comprehensive pathway driving CMF formation in conjunction with TGF-, Ca influx, CaN, NFATc3, and DYRK1A.
心肌成纤维细胞（CFs）是一种关键的细胞群体，负责心肌细胞外基质的动态平衡。在心肌梗死（MI）刺激后，CFs 向心肌成纤维细胞（CMFs）转分化，并在纤维化愈合反应中发挥重要作用。瞬时受体电位锚蛋白 1（TRPA1）通道是阳离子离子通道，具有较高的 Ca 电流分数，已知其在 MI 损伤后会影响心脏功能；然而，调节 CMF 转分化的分子机制仍知之甚少。TRPA1 敲除小鼠、其野生型同窝仔鼠和用 TRPA1 激动剂肉桂醛（CA）预处理的小鼠接受 MI 损伤，并监测其存活、心脏功能和纤维化重塑。TRPA1 可在 MI 损伤后 1 周驱动成纤维细胞转分化。此外，我们通过单独转染或与抑制剂联合处理的实验，探索了潜在的机制。TRPA1 过表达可完全激活 CMF 转化，而缺乏 TRPA1 的 CFs 则对转化生长因子 - (TGF--) 诱导的转分化无反应。TGF-增强了 TRPA1 的表达，促进了钙调神经磷酸酶（CaN）的 Ca 反应性激活。此外，双特异性酪氨酸调节激酶-1a（DYRK1A）调节 CaN 介导的 NFAT 核易位和 TRPA1 依赖性转分化。这些发现表明 TRPA1 在调节 MI 损伤后 CMF 转分化方面具有潜在的治疗作用，并表明与 TGF-、Ca 内流、CaN、NFATc3 和 DYRK1A 一起驱动 CMF 形成的综合途径。
