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
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2022,（3）
• 所属期刊栏目: Cardiovascular Pharmacology
• 页码范围: 602-612
• 页数: 11页
• 语种: 英文

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.