miR-194 ameliorates hepatic ischemia/reperfusion injury via targeting PHLDA1 in a TRAF6-dependent manner

作者全名："Luo, Yun-Hai; Huang, Zuo-Tian; Zong, Ke-Zhen; Cao, Zhen-Rui; Peng, Da-Di; Zhou, Bao-Yong; Shen, Ai; Yan, Ping; Wu, Zhong-Jun"

作者地址："[Luo, Yun-Hai; Huang, Zuo-Tian; Zong, Ke-Zhen; Cao, Zhen-Rui; Peng, Da-Di; Zhou, Bao-Yong; Yan, Ping; Wu, Zhong-Jun] Chongqing Med Univ, Affiliated Hosp 1, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Shen, Ai] Chongqing Univ, Canc Hosp, Hepatobiliary Pancreat Tumor Ctr, Chongqing 400030, Peoples R China"

通信作者："Wu, ZJ (corresponding author), Chongqing Med Univ, Affiliated Hosp 1, 1 Youyi Rd, Chongqing 400016, Peoples R China."

来源：INTERNATIONAL IMMUNOPHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000664066000005

JCR分区：Q1

影响因子：5.6

年份：2021

卷号：96

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Ischemia; Reperfusion; PHLDA1; miR-194; IKK; Inflammation

摘要："Hepatic ischemia/reperfusion injury (IRI) is an inevitable pathological process in liver resection, shock and transplantation. However, the internal mechanism of hepatic IRI, including inflammatory transduction of multiple signaling pathways, is not fully understood. In the present study, we identified pleckstrin homology-like domain family member 1 (PHLDA1), suppressed by microRNA (miR)-194, as a critical intersection of dual inflammatory signals in hepatic IRI. PHLDA1 was upregulated in hepatic IRI with a concomitant downregulation of miR-194. Overexpression of miR-194 diminished PHLDA1 and inhibitors of the nuclear factor kappa-B kinase (IKK) pathway, thus leading to remission of hepatic pathological injury, apoptosis and release of cytokines. Further enrichment of PHLDA1 reversed the function of miR-194 both in vivo and in vitro. For an in-depth query, we verified PHLDA1 as a direct target of miR-194. Notably, inflammatory signal transduction of PHLDA1 was induced by activating TNF receptor-associated factor 6 (TRAF6), sequentially initiating IKK and mitogenactivated protein kinase (MAPK), both of which aggravate stress and inflammation in hepatic IRI. In conclusion, the miR-194/PHLDA1 axis was a key upstream regulator of IKK and MAPK in hepatic IRI. Targeting PHLDA1 might be a potential strategy for hepatic IRI therapy."

基金机构："National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81873592]; graduate tutor team construction project of Chongqing Municipal Education Commission Foundation, China [dstd201801]; Natural Science Foundation of Yuzhong district, Chongqing, China [20180102]"

基金资助正文："This study was supported by the National Natural Science Foundation of China (No. 81873592) , the graduate tutor team construction project of Chongqing Municipal Education Commission Foundation, China (No. dstd201801) and Natural Science Foundation of Yuzhong district, Chongqing, China (No. 20180102) ."