ADAR1 regulates vascular remodeling in hypoxic pulmonary hypertension through N1-methyladenosine modification of circCDK17  

作　　者：Junting Zhang Yiying Li Jianchao Zhang Lu Liu Yuan Chen Xusheng Yang Xueyi Liao Muhua He Zihui Jia Jun Fan Jin-Song Bian Xiaowei Nie 

机构地区：[1]Shenzhen Institute of Respiratory Disease,Shenzhen Key Laboratory of Respiratory Disease,Shenzhen People's Hospital(the Second Clinical Medical College,Jinan University,the First Afiliated Hospital,Southern University of Science and Technology),Shenzhen 518020,China [2]Post-Doctoral Scientific Research Station of Basic Medicine,JinanUniversity,Guangzhou 510632,China [3]Department of Pharmacology,School of Medicine,Southern University of Science and Technology,Shenzhen 518055,China [4]Lung Transplant Group,Wuxi People's Hospital Affliated to Nanjing Medical University,Wuxi 211103,China [5]Department of Medical Biochemistry and Molecular Biology,School of Medicine,Jinan University,Guangzhou 510632,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第12期4840-4855,共16页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(NSFC),China(Grant No 82170064,82241021 to Xiaowei Nie);Shenzhen Excellent Science and Technology Innovation Talent Development Programme,Shenzhen,China(Grant No.RCJC20210706091946002 to Xiaowei Nie);Shenzhen Science and Technology Program,Shenzhen,China(Grant No.JSGGZD20220822095200001 to Jin-Song Bian);China Postdoctoral Science Foundation,China(Grant No.2022M722212 to Junting Zhang).

摘　　要：Pulmonary hypertension(PH)is an extremely malignant pulmonary vascular disease of unknown etiology.ADAR1 is an RNA editing enzyme that converts adenosine in RNA to inosine,thereby affecting RNA expression.However,the role of ADAR1 in PH development remains unclear.In the present study,we investigated the biological role and molecular mechanism of ADAR1 in PH pulmonary vascular remodeling.Overexpression of ADAR1 aggravated PH progression and promoted the proliferation of pulmonary artery smooth muscle cells(PASMCs).Conversely,inhibition of ADAR1 produced opposite effects.High-throughput whole transcriptome sequencing showed that ADAR1 was an important regulator of circRNAs in PH.CircCDK17 level was significantly lowered in the serum of PH patients.The effects of ADAR1 on cell cycle progression and proliferation were mediated by circCDK17.ADAR1 affects the stability of circCDK17 by mediating A-to-I modification at the A5 and A293 sites of circCDK17 to prevent it from mlA modification.We demonstrate for the first time that ADAR1 contributes to the PH development,at least partially,through m1A modification of circCDK17 and the subsequent PASMCs proliferation.Our study provides a novel therapeutic strategy for treatment of PH and the evidence for circCDK17 as a potential novel marker for the diagnosis of this disease.

关 键 词：Pulmonary hypertension ADAR1 Circular RNA Vascular remodeling Cell proliferation 

分 类 号：R51[医药卫生—内科学]