ZEB1-AS1 as a TRPML1 Inhibitor to Cause Lysosome Dysfunction and Cardiac Damage in Aged Mice  

作　　者：Heng Liu Haiying Zhang Han Lou Jennifer Wang Shengxin Hao Hui Chen Chen Chen Lei Wang Huimin Li Ziyu Meng Wenjie Zhao Tong Zhao Yuan Lin Zhimin Du Xin Liu Baofeng Yang Yong Zhang 

机构地区：[1]State Key Laboratory of Frigid Zone Cardiovascular Diseases(SKLFZCD),College of Pharmacy,and Department of Cardiology,the Second Affiliated Hospital,Harbin Medical University,Harbin 150081,China [2]Pharmaceutical Experiment Teaching Center,College of Pharmacy,Harbin Medical University,Harbin 150081,China [3]Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education,School of Pharmacy,Hainan Medical University,Haikou 571199,China [4]Department of Pharmacology(SKLFZCD,State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China,Key Laboratory of Cardiovascular Research,Ministry of Education),College of Pharmacy,Harbin Medical University,Harbin 150081,China [5]Research Unit of Noninfectious Chronic Diseases in Frigid Zone(2019RU070),Chinese Academy of Medical Sciences,Harbin 150081,China [6]Department of Medicine,Faculty of Medicine,Universitéde Laval,Quebec City,G1V 0A6,Canada [7]University Key Laboratory of Drug Research,Heilongjiang Province,Institute of Clinical Pharmacology,The Second Affiliated Hospital of Harbin Medical University,Harbin 150086,China [8]Department of Clinical Pharmacology,College of Pharmacy,Harbin Medical University,Harbin 150081,China [9]State Key Laboratory of Quality Research in Chinese Medicines,Macao University of Science and Technology,Macao 999078,China

出　　处：《Engineering》2024年第12期183-200,共18页工程(英文)

基　　金：funded by the National Natural Science Foundation of China(82273919,82270396,and U21A20339);the China Postdoctoral Science Foundation(2023T160176)。

摘　　要：The prevalence of cardiovascular diseases(CVDs)has increased markedly as the world population has aged.Long non-coding RNAs(lncRNAs)have been reported as novel regulators in diverse pathophysiological conditions.Here,we performed RNA sequencing(RNA-seq)and observed that the lncRNA Zeb1os1(zinc finger E-box binding homeobox 1,opposite strand 1),which is known as ZEB1-AS1(zinc finger E-box binding homeobox 1 antisense 1)in humans,was upregulated in the aged mice hearts,senescent cardiomyocytes,and human blood from elderly individuals.The human blood ZEB1-AS1 level was positively relevant to human age but negatively relevant to peak E to peak A(E/A).Silencing Zeb1os1 ameliorated diastolic dysfunction and cardiac senescence in aged mice.On the other hand,Zeb1os1 overexpression triggered cardiac dysfunction resembling that observed in aged mice.Mechanistically,we provide compelling evidence that Zeb1os1 interacts with the transient receptor potential mucolipin 1(TRPML1)for ubiquitination(UB)-mediated degradation.This process inhibits lysosomal Ca^(2+)efflux,impairing lysosome function.In addition,the functional domain of Zeb1os1,which contains the key nucleotides responsible for the pro-senescence property of full-length Zeb1os1 in cardiomyocytes.Together,these data suggest that Zeb1os1 is a potential target for ameliorating lysosomal dysfunction and aging-related cardiac impairment.

关 键 词：Heart aging Cardiomyocytes senescence ZEB1-AS1 TRPML1 LYSOSOME 

分 类 号：R541[医药卫生—心血管疾病]