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The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis
- Source :
- International Journal of Molecular Sciences, Volume 22, Issue 4, International Journal of Molecular Sciences, Vol 22, Iss 1861, p 1861 (2021)
- Publication Year :
- 2021
-
Abstract
- Background: Pathological activation of cardiac fibroblasts is a key step in development and progression of cardiac fibrosis and heart failure. This process has been associated with enhanced autophagocytosis, but molecular mechanisms remain largely unknown. Methods and Results: Immunohistochemical analysis of endomyocardial biopsies showed increased activation of autophagy in fibrotic hearts of patients with inflammatory cardiomyopathy. In vitro experiments using mouse and human cardiac fibroblasts confirmed that blockade of autophagy with Bafilomycin A1 inhibited fibroblast-to-myofibroblast transition induced by transforming growth factor (TGF)-β. Next, we observed that cardiac fibroblasts obtained from mice overexpressing transcription factor Fos-related antigen 2 (Fosl-2tg) expressed elevated protein levels of autophagy markers: the lipid modified form of microtubule-associated protein 1A/1B-light chain 3B (LC3BII), Beclin-1 and autophagy related 5 (Atg5). In complementary experiments, silencing of Fosl-2 with antisense GapmeR oligonucleotides suppressed production of type I collagen, myofibroblast marker alpha smooth muscle actin and autophagy marker Beclin-1 in cardiac fibroblasts. On the other hand, silencing of either LC3B or Beclin-1 reduced Fosl-2 levels in TGF-β-activated, but not in unstimulated cells. Using a cardiac hypertrophy model induced by continuous infusion of angiotensin II with osmotic minipumps, we confirmed that mice lacking either Fosl-2 (Ccl19CreFosl2flox/flox) or Atg5 (Ccl19CreAtg5flox/flox) in stromal cells were protected from cardiac fibrosis. Conclusion: Our findings demonstrate that Fosl-2 regulates autophagocytosis and the TGF-β-Fosl-2-autophagy axis controls differentiation of cardiac fibroblasts. These data provide a new insight for the development of pharmaceutical targets in cardiac fibrosis.
- Subjects :
- Male
Cardiac fibrosis
cardiac fibrosis
1607 Spectroscopy
Fos-Related Antigen-2
lcsh:Chemistry
Mice
0302 clinical medicine
lcsh:QH301-705.5
Spectroscopy
cardiac fibroblasts
0303 health sciences
Chemistry
cardiac hypertrophy
10051 Rheumatology Clinic and Institute of Physical Medicine
General Medicine
Middle Aged
3. Good health
Computer Science Applications
AP-1 transcription factor
030220 oncology & carcinogenesis
Female
1606 Physical and Theoretical Chemistry
Myofibroblast
autophagy
Stromal cell
1503 Catalysis
ATG5
Mice, Transgenic
610 Medicine & health
Article
Catalysis
Inorganic Chemistry
03 medical and health sciences
medicine
1312 Molecular Biology
1706 Computer Science Applications
Animals
Humans
Physical and Theoretical Chemistry
Molecular Biology
Fos-related antigen 2
030304 developmental biology
Aged
Heart Failure
1604 Inorganic Chemistry
Myocardium
Organic Chemistry
Autophagy
Fibroblasts
medicine.disease
Angiotensin II
Fibrosis
Transcription Factor AP-1
lcsh:Biology (General)
lcsh:QD1-999
Gene Expression Regulation
Cancer research
Transforming growth factor
1605 Organic Chemistry
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences, Volume 22, Issue 4, International Journal of Molecular Sciences, Vol 22, Iss 1861, p 1861 (2021)
- Accession number :
- edsair.doi.dedup.....82e7c69209c14bf1317aaed611b7e73b