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Resistin induces cardiac fibroblast-myofibroblast differentiation through JAK/STAT3 and JNK/c-Jun signaling
- Source :
- Pharmacol Res
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- Cardiac fibrosis is characterized by excessive deposition of extracellular matrix proteins and myofibroblast differentiation. Our previous findings have implicated resistin in cardiac fibrosis; however, the molecular mechanisms underlying this process are still unclear. Here we investigated the role of resistin in fibroblast-to-myofibroblast differentiation and elucidated the pathways involved in this process. Fibroblast-to-myofibroblast transdifferentiation was induced with resistin or TGFβ1 in NIH-3T3 and adult cardiac fibroblasts. mRNA and protein expression of fibrotic markers were analyzed by qPCR and immunoblotting. Resistin-knockout mice, challenged with a high-fat diet (HFD) for 20 weeks to stimulate cardiac impairment, were analyzed for cardiac function and fibrosis using histologic and molecular methods. Cardiac fibroblasts stimulated with resistin displayed increased fibroblast-to-myofibroblast conversion, with increased levels of αSma, col1a1, Fn, Ccn2 and Mmp9, with remarkable differences in the actin network appearance. Mechanistically, resistin promotes fibroblast-to-myofibroblast transdifferentiation and fibrogenesis via JAK2/STAT3 and JNK/c-Jun signaling pathways, independent of TGFβ1. Resistin-null mice challenged with HFD showed an improvement in cardiac function and a decrease in tissue fibrosis and reduced mRNA levels of fibrogenic markers. These findings are the first to delineate the role of resistin in the process of cardiac fibroblast-to-myofibroblast differentiation via JAK/STAT3 and JNK/c-Jun pathways, potentially leading to stimulation of cardiac fibrosis.
- Subjects :
- Male
STAT3 Transcription Factor
0301 basic medicine
Cardiac function curve
MAP Kinase Signaling System
Cardiac fibrosis
Article
Extracellular matrix
Mice
03 medical and health sciences
0302 clinical medicine
Fibrosis
medicine
Animals
Humans
Myocytes, Cardiac
Resistin
Janus Kinases
Mice, Knockout
Pharmacology
business.industry
Transdifferentiation
JNK Mitogen-Activated Protein Kinases
nutritional and metabolic diseases
Fibroblasts
medicine.disease
Mice, Inbred C57BL
HEK293 Cells
030104 developmental biology
030220 oncology & carcinogenesis
Cell Transdifferentiation
NIH 3T3 Cells
Cancer research
Female
Myocardial fibrosis
business
Myofibroblast
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- ISSN :
- 10436618
- Volume :
- 167
- Database :
- OpenAIRE
- Journal :
- Pharmacological Research
- Accession number :
- edsair.doi.dedup.....f4a0b94c38e2730ae9cb94e4931eefe1