S-nitrosylation of c-Jun N-terminal kinase mediates pressure overload-induced cardiac dysfunction and fibrosis  

作　　者：Miao Zhou Ji-yu Chen Meng-Lin Chao Chao Zhang Zhi-guang Shi Xue-chun Zhou Li-ping Xie Shi-xiu Sun Zheng-rong Huang Shan-shan Luo Yong Ji 

机构地区：[1]Key Laboratory of Cardiovascular and Cerebrovascular Medicine,Nanjing Medical University,Nanjing 201203,China [2]Key Laboratory of Targeted Intervention of Cardiovascular Disease,Collaborative Innovation Center for Cardiovascular Disease Translational Medicine,Nanjing Medical University,Nanjing 201203,China [3]Department of Cardiology,the First Affiliated Hospital of Xiamen University,Xiamen 361003,China [4]State Key Laboratory of Reproductive Medicine,Nanjing Medical University,Nanjing 201203,China

出　　处：《Acta Pharmacologica Sinica》2022年第3期602-612,共11页中国药理学报（英文版）

基　　金：This work was supported by grants from the National Key Research and Development Program of China(2019YFA0802704);National Natural Science Foundation of China(grant NOs.82030013,81820108002,81800213,81870183);Natural Science Foundation of Jiangsu Province(BK20180680);Natural Science Foundation of Jiangsu Higher Education Institutions of China(19KJA360004).

摘　　要：Cardiac fibrosis(CF)is an irreversible pathological process that occurs in almost all kinds of cardiovascular diseases.Phosphorylation-dependent activation of c-Jun N-terminal kinase(JNK)induces cardiac fibrosis.However,whether S-nitrosylation of JNK mediates cardiac fibrosis remains an open question.A biotin-switch assay confirmed that S-nitrosylation of JNK(SNO-JNK)increased significantly in the heart tissues of hypertrophic patients,transverse aortic constriction(TAC)mice,spontaneously hypertensive rats(SHRs),and neonatal rat cardiac fibroblasts(NRCFs)stimulated with angiotensin II(Ang II).Site to site substitution of alanine for cysteine in JNK was applied to determine the S-nitrosylated site.S-Nitrosylation occurred at both Cys116 and Cys163 and substitution of alanine for cysteine 116 and cysteine 163(C116/163A)inhibited Ang II-induced myofibroblast transformation.We further confirmed that the source of S-nitrosylation was inducible nitric oxide synthase(iNOS).1400 W,an inhibitor of iNOS,abrogated the profibrotic effects of Ang II in NRCFs.Mechanistically,SNO-JNK facilitated the nuclear translocation of JNK,increased the phosphorylation of c-Jun,and induced the transcriptional activity of AP-1 as determined by chromatin immunoprecipitation and EMSA.Finally,WT and iNOS−/−mice were subjected to TAC and iNOS knockout reduced SNO-JNK and alleviated cardiac fibrosis.Our findings demonstrate an alternative mechanism by which iNOS-induced SNO-JNK increases JNK pathway activity and accelerates cardiac fibrosis.Targeting SNO-JNK might be a novel therapeutic strategy against cardiac fibrosis.

关 键 词：cardiac fibrosis S-NITROSYLATION transcriptional activation JNK INOS 

分 类 号：R54[医药卫生—心血管疾病]