廖杰, 杨帅涛, 卢凯, 路阳, 吴雨薇, 杜以梅*
钙稳态失衡，主要涉及雷诺丁受体(ryanodine receptor, RyR)和肌浆网钙离子ATP酶(sarcoplasmic reticulum Ca2+-ATPase, SERCA)等功能异常，是心房颤动(atrial fibrillation, AF)的一种重要发病机制。本课题组前期已发现瞬时感受器电位离子通道家族香草素受体亚家族4 (transient receptor potential vanilloid subtype 4, TRPV4)在无菌性心包炎(sterile pericarditis, SP) AF大鼠模型中表达和功能上调，口服TRPV4抑制剂GSK2193874缓解SP大鼠的AF发作。本文旨在探讨口服GSK2193874是否缓解SP大鼠的钙稳态失衡。Sprague-Dawley (SD)大鼠在进行心包切开术后，将无菌性滑石粉均匀涂抹在心房上以创建SP模型，模拟术后心房颤动(postoperative atrial fibrillation, POAF)的发病过程。于术后第3天，利用光学标测(optical mapping)技术采集心房钙信号，检测钙瞬变时程(Ca2+ transient duration, CaD)、交替(alternan)和钙瞬变恢复情况。结果显示，口服GSK2193874不仅改善SP大鼠心房组织表面达峰时间(time to peak，主要反映RyR Ca2+释放功能)和CaD的延长(主要反映SERCA Ca2+回收功能)以及CaD的异常分布，还缓解SP大鼠心房alternan，进而减少不和谐交替(discordant alternan, DIS-ALT)的发生。尤为重要的是，口服GSK2193874抑制SP大鼠心房钙瞬变恢复比例(主要反映RyR不应性)降低，并减轻其在心房表面的分布异质性。以上结果提示，口服TRPV4抑制剂主要通过阻断TRPV4-Ca2+-RyR途径缓解钙稳态失衡，进而达到治疗POAF的效果。
Oral administration of TRPV4 inhibitor improves atrial calcium handling abnormalities in sterile pericarditis rats
LIAO Jie, YANG Shuai-Tao, LU Kai, LU Yang, WU Yu-Wei, DU Yi-Mei*
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Atrial Ca2+ handling abnormalities, mainly involving the dysfunction of ryanodine receptor (RyR) and sarcoplasmic reticulum Ca2+-ATPase (SERCA), play a role in the pathogenesis of atrial fibrillation (AF). Previously, we found that the expression and function of transient receptor potential vanilloid subtype 4 (TRPV4) are upregulated in a sterile pericarditis (SP) rat model of AF, and oral administration of TRPV4 inhibitor GSK2193874 alleviates AF in this animal model. The aim of this study was to investigate whether oral administration of GSK2193874 could alleviate atrial Ca2+ handling abnormalities in SP rats. A SP rat model of AF was established by daubing sterile talcum powder on both atria of Sprague-Dawley (SD) rats after a pericardiotomy, to simulate the pathogenesis of postoperative atrial fibrillation (POAF). On the 3rd postoperative day, Ca2+ signals of atria were collected in isolated perfused hearts by optical mapping. Ca2+ transient duration (CaD), alternan, and the recovery properties of Ca2+ transient (CaT) were quantified and analyzed. GSK2193874 treatment reversed the abnormal prolongation of time to peak (determined mainly by RyR activity) and CaD (determined mainly by SERCA activity), as well as the regional heterogeneity of CaD in SP rats. Furthermore, GSK2193874 treatment relieved alternan in SP rats, and reduced its incidence of discordant alternan (DIS-ALT). More importantly, GSK2193874 treatment prevented the reduction of the S2/S1 CaT ratio (determined mainly by RyR refractoriness) in SP rats, and decreased its regional heterogeneity. Taken together, oral administration of TRPV4 inhibitor alleviates Ca2+ handling abnormalities in SP rats primarily by blocking the TRPV4-Ca2+-RyR pathway, and thus exerts therapeutic effect on POAF.
通讯作者：杜以梅 E-mail: firstname.lastname@example.org
廖杰, 杨帅涛, 卢凯, 路阳, 吴雨薇, 杜以梅. 口服TRPV4抑制剂改善无菌性心包炎大鼠心房钙稳态失衡[J]. 生理学报 2022; 74 (2): 188-200.
LIAO Jie, YANG Shuai-Tao, LU Kai, LU Yang, WU Yu-Wei, DU Yi-Mei. Oral administration of TRPV4 inhibitor improves atrial calcium handling abnormalities in sterile pericarditis rats. Acta Physiol Sin 2022; 74 (2): 188-200 (in Chinese with English abstract).