Back to Search
Start Over
S-nitrosylation of c-Jun N-terminal kinase mediates pressure overload-induced cardiac dysfunction and fibrosis
- Source :
- Acta Pharmacol Sin
- Publication Year :
- 2021
- Publisher :
- Springer Singapore, 2021.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Heart Diseases
Cardiac fibrosis
Nitric Oxide Synthase Type II
Pharmacology
Article
03 medical and health sciences
Mice
0302 clinical medicine
Fibrosis
Rats, Inbred SHR
medicine
Animals
Humans
Pharmacology (medical)
Aorta
Pressure overload
Mice, Knockout
biology
Chemistry
Angiotensin II
c-jun
JNK Mitogen-Activated Protein Kinases
General Medicine
S-Nitrosylation
Fibroblasts
medicine.disease
Rats
Nitric oxide synthase
Mice, Inbred C57BL
030104 developmental biology
030220 oncology & carcinogenesis
biology.protein
Imines
Myofibroblast
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Acta Pharmacol Sin
- Accession number :
- edsair.doi.dedup.....c0aa6ef43ab79b4c96fad70b2da21838