microRNA-454-mediated NEDD4-2/TrkA/cAMP axis in heart failure: Mechanisms and cardioprotective implications

作者全名："Wang, Yaowen; Pan, Wei; Bai, Xinyu; Wang, Xukai; Wang, Yan; Yin, Yuehui"

作者地址："[Wang, Yaowen; Pan, Wei; Yin, Yuehui] Chongqing Med Univ, Dept Cardiol, Chongqing Cardiac Arrhythmias Therapeut Serv Ctr, Affiliated Hosp 2, 74 Linjiang Rd, Chongqing 400010, Peoples R China; [Bai, Xinyu; Wang, Yan] Zunyi Med Univ, Key Lab Basic Pharmacol, Minist Educ, 6 Xuefu West Rd, Zunyi 563000, Guizhou, Peoples R China; [Bai, Xinyu; Wang, Yan] Zunyi Med Univ, Joint Int Res Lab Ethnomed, Minist Educ, 6 Xuefu West Rd, Zunyi 563000, Guizhou, Peoples R China; [Bai, Xinyu] Army Med Univ, Inst Field Surg, Daping Hosp, Dept Cardiol, Chongqing, Peoples R China"

通信作者："Yin, YH (corresponding author), Chongqing Med Univ, Dept Cardiol, Chongqing Cardiac Arrhythmias Therapeut Serv Ctr, Affiliated Hosp 2, 74 Linjiang Rd, Chongqing 400010, Peoples R China.; Wang, Y (corresponding author), Zunyi Med Univ, Key Lab Basic Pharmacol, Minist Educ, 6 Xuefu West Rd, Zunyi 563000, Guizhou, Peoples R China.; Wang, Y (corresponding author), Zunyi Med Univ, Joint Int Res Lab Ethnomed, Minist Educ, 6 Xuefu West Rd, Zunyi 563000, Guizhou, Peoples R China."

来源：JOURNAL OF CELLULAR AND MOLECULAR MEDICINE

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000647057700001

JCR分区：Q2

影响因子：5.3

年份：2021

卷号：25

期号：11

开始页：5082

结束页：5098

文献类型：Article

关键词：apoptosis; cAMP pathway; heart failure; microRNA‐ 454; NEDD4‐ 2; oxidative stress; TrkA

摘要："The current study aimed to investigate the mechanism by which miR-454 influences the progression of heart failure (HF) in relation to the neural precursor cell expressed, developmentally downregulated 4-2 (NEDD4-2)/tropomyosin receptor kinase A (TrkA)/cyclic adenosine 3',5'-monophosphate (cAMP) axis. Sprague-Dawley rats were used to establish a HF animal model via ligation of the left anterior descending branch of the coronary artery. The cardiomyocyte H9c2 cells were treated with H2O2 to stimulate oxidative stress injury in vitro. RT-qPCR and Western blot assay were subsequently performed to determine the expression patterns of miR-454, NEDD4-2, TrkA, apoptosis-related proteins and cAMP pathway markers. Dual-luciferase reporter gene assay coupled with co-immunoprecipitation was performed to elucidate the relationship between miR-454, NEDD4-2 and TrkA. Gain- or loss-of-function experiments as well as rescue experiments were conducted via transient transfection (in vitro) and adenovirus infection (in vivo) to examine their respective functions on H9c2 cell apoptosis and myocardial damage. Our results suggested that miR-454 was aberrantly downregulated in the context of HF, while evidence was obtained suggesting that it targeted NEDD4-2 to downregulate NEDD4-2 in cardiomyocytes. miR-454 exerted anti-apoptotic and protective effects on cardiomyocytes through inhibition of NEDD4-2, while NEDD4-2 stimulated ubiquitination and degradation of TrkA protein. Furthermore, miR-454 activated the cAMP pathway via the NEDD4-2/TrkA axis, which ultimately suppressed cardiomyocyte apoptosis and attenuated myocardial damage. Taken together, the key findings of the current study highlight the cardioprotective role of miR-454, which is achieved through activation of the cAMP pathway by impairing NEDD4-2-induced TrkA ubiquitination."

基金机构：National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81860643]

基金资助正文："National Natural Science Foundation of China, Grant/Award Number: 81860643"