Hypoxia-stimulated cardiac fibroblast production of IL-6 promotes myocardial fibrosis via the TGF-β1 signaling pathway

Autor: Shaoheng Zhang, Nannan Chen, Jian Yan, Jiahong Wang, Lan Zhao, Jian Chen, Yan Zhang, Feng Su, Xin Pan, Qunlin Gong
Rok vydání: 2015
Předmět:
0301 basic medicine
MMP2
Angiogenesis
medicine.medical_treatment
Receptor
Transforming Growth Factor-beta Type I
Apoptosis
030204 cardiovascular system & hematology
0302 clinical medicine
Fibrosis
Myocytes
Cardiac
Receptor
Hypoxia
Myofibroblasts
Cells
Cultured
Models
Cardiovascular
Cell biology
Up-Regulation
Cytokine
Matrix Metalloproteinase 9
Matrix Metalloproteinase 2
Signal transduction
Signal Transduction
medicine.medical_specialty
Neovascularization
Physiologic
Matrix Metalloproteinase Inhibitors
Protein Serine-Threonine Kinases
Pathology and Forensic Medicine
Transforming Growth Factor beta1
03 medical and health sciences
Downregulation and upregulation
Internal medicine
medicine
Animals
Molecular Biology
Cell Proliferation
business.industry
Interleukin-6
Myocardium
Endothelial Cells
Cell Biology
Fibroblasts
medicine.disease
Receptors
Interleukin-6
Coculture Techniques
Rats
030104 developmental biology
Endocrinology
Myocardial fibrosis
sense organs
business
Receptors
Transforming Growth Factor beta
Zdroj: Laboratory investigation; a journal of technical methods and pathology. 96(8)
ISSN: 1530-0307
Popis: Interlukin-6 (IL-6) is a multifunctional cytokine produced by several cell types that has a role in fibrosis. Fibroblasts (FBs) maintain this underlying pathogenic change through regulation of IL-6 production; however, its potential functional role in regulating surrounding cellular structural changes during ischemic myocardial remodeling remains unexplored. Here, we generated FBs, cardiomyocytes (CMs), and blood vascular endothelial cells (ECs) from the ventricles of neonatal rats. IL-6 was then overexpressed in FBs and the cells were treated with IL-6 receptor inhibitor (IL6RI), TGF-β1 receptor inhibitor (TβRI), or MMP2/MMP9 inhibitor (MMPI) using monoculture or coculture models under hypoxic conditions. The results indicate that overexpression of IL-6 is sufficient to induce myofibroblastic proliferation, differentiation, and fibrosis, probably via increased TGF-β1-mediated MMP2/MMP3 signaling. The use of IL6RI, TβRI, or MMPI diminished these effects. In addition, IL-6 activated the apoptosis-associated factors Caspase3 and Smad3, and decreased the expression of anti-apoptotic factor Bcl2, resulting in apoptosis of CMs under hypoxic coculture: IL6RI or TβRI inhibited these effects. Unexpectedly, IL-6-overexpressing FBs significantly increased the angiogenesis of ECs, which involved significant increases in the expression of proangiogenic growth factors. Treatment of FBs with IL6RI or TβRI in coculture with ECs reduced the levels of secreted proangiogenic growth factors, and the angiogenesis of ECs was significantly downregulated. Thus, IL-6 functions in ischemic myocardial remodeling through multifunctional reprogramming of hypoxia-associated FBs towards fibrosis via upregulation of the TGF-β1 signaling pathway.
Databáze: OpenAIRE
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