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Ubiquitin carboxyl terminal hydrolyase L1-suppressed autophagic degradation of p21WAF1/Cip1 as a novel feedback mechanism in the control of cardiac fibroblast proliferation.
- Source :
-
PloS one [PLoS One] 2014 Apr 14; Vol. 9 (4), pp. e94658. Date of Electronic Publication: 2014 Apr 14 (Print Publication: 2014). - Publication Year :
- 2014
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Abstract
- Aims: Deubiquitinating enzymes (DUBs) appear to be critical regulators of a multitude of processes such as proliferation, apoptosis, differentiation, and inflammation; however, the potential roles of DUBs in the heart remain to be determined. This study was aimed to explore the role of a DUB, ubiquitin carboxyl terminal hydrolyase L1 (UCH-L1) in maladaptive cardiac remodeling and dysfunction.<br />Methods and Results: Maladaptive cardiac remodeling and dysfunction were induced in mice by transverse aortic constriction (TAC). UCH-L1 expression was transiently increased and then declined near to the basal level while impairment of cardiac function proceeded. The upregulation of UCH-L1 was observed in cardiac myocytes and fibroblasts. In primary culture of cardiac fibroblasts, UCH-L1 was upregulated by platelet-derived growth factor (PDGF)-BB and PDGF-DD. Adenoviral overexpession of UCH-L1 inhibited the PDGF-induced cardiac fibroblast proliferation without affecting the activation of mitogen activated protein kinases (MAPKs), Akt, and signal transducers and activators of transcription 3 (STAT3). Further signaling dissection revealed that PDGF-BB posttranscriptional upregulated p21WAF1/Cip1 protein expression, which was inhibited by rapamycin, an activator of autophagy via suppressing mammalian target of rapamycin (mTOR), rather than MG132, a proteasome inhibitor. Overexpression of UCH-L1 enhanced PDGF-BB-induced mTOR phosphorylation and upregulation of p21WAF1/Cip1 protein expression while suppressed autophagic flux in cardiac fibroblasts.<br />Conclusion: UCH-L1 facilitates PDGF-BB-induced suppression of autophagic degradation of p21WAF1/Cip1 proteins in cardiac fibroblasts, which may serve as a novel negative feedback mechanism in the control of cardiac fibroblast proliferation contributing to cardiac fibrosis and dysfunction.
- Subjects :
- Animals
Animals, Newborn
Aorta pathology
Becaplermin
Cell Proliferation
Fibroblasts metabolism
Flow Cytometry
Lymphokines metabolism
Male
Mice
Mice, Inbred C57BL
Phosphorylation
Platelet-Derived Growth Factor metabolism
Protein Structure, Tertiary
Proto-Oncogene Proteins c-sis metabolism
Rats
STAT3 Transcription Factor metabolism
Signal Transduction
Sincalide metabolism
Up-Regulation
Ventricular Remodeling
Autophagy
Cyclin-Dependent Kinase Inhibitor p21 metabolism
Fibroblasts cytology
Myocardium enzymology
Ubiquitin Thiolesterase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 9
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 24732420
- Full Text :
- https://doi.org/10.1371/journal.pone.0094658