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Cathepsin S Activity Controls Injury-Related Vascular Repair in Mice via the TLR2-Mediated p38MAPK and PI3K-Akt/p-HDAC6 Signaling Pathway
- Source :
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Publication Year :
- 2015
-
Abstract
- Supplemental Digital Content is available in the text.<br />Objective— Cathepsin S (CatS) participates in atherogenesis through several putative mechanisms. The ability of cathepsins to modify histone tail is likely to contribute to stem cell development. Histone deacetylase 6 (HDAC6) is required in modulating the proliferation and migration of various types of cancer cells. Here, we investigated the cross talk between CatS and HADC6 in injury-related vascular repair in mice. Approach and Results— Ligation injury to the carotid artery in mice increased the CatS expression, and CatS-deficient mice showed reduced neointimal formation in injured arteries. CatS deficiency decreased the phosphorylation levels of p38 mitogen-activated protein kinase, Akt, and HDAC6 and toll-like receptor 2 expression in ligated arteries. The genetic or pharmacological inhibition of CatS also alleviated the increased phosphorylation of p38 mitogen-activated protein kinase, Akt, and HDAC6 induced by platelet-derived growth factor BB in cultured vascular smooth muscle cells (VSMCs), and p38 mitogen-activated protein kinase inhibition and Akt inhibition decreased the phospho-HDAC6 levels. Moreover, CatS inhibition caused decrease in the levels of the HDAC6 activity in VSMCs in response to platelet-derived growth factor BB. The HDAC6 inhibitor tubastatin A downregulated platelet-derived growth factor–induced VSMC proliferation and migration, whereas HDAC6 overexpression exerted the opposite effect. Tubastatin A also decreased the intimal VSMC proliferation and neointimal hyperplasia in response to injury. Toll-like receptor 2 silencing decreased the phosphorylation levels of p38 mitogen-activated protein kinase, Akt, and HDAC6 and VSMC migration and proliferation. Conclusions— This is the first report detailing cross-interaction between toll-like receptor 2–mediated CatS and HDAC6 during injury-related vascular repair. These data suggest that CatS/HDAC6 could be a potential therapeutic target for the control of vascular diseases that are involved in neointimal lesion formation.
- Subjects :
- 0301 basic medicine
Male
medicine.medical_treatment
030204 cardiovascular system & hematology
Histone Deacetylase 6
p38 Mitogen-Activated Protein Kinases
Muscle, Smooth, Vascular
0302 clinical medicine
Cell Movement
Phosphorylation
Cells, Cultured
Neointimal hyperplasia
Mice, Knockout
CATS
Phenotype
cathepsin S
ComputingMethodologies_DOCUMENTANDTEXTPROCESSING
RNA Interference
Signal transduction
Cardiology and Cardiovascular Medicine
Signal Transduction
Genotype
Carotid Artery, Common
vascular remodeling
Myocytes, Smooth Muscle
Biology
Transfection
Histone Deacetylases
03 medical and health sciences
Neointima
medicine
Animals
Protease Inhibitors
neointimal formation
Protein kinase A
Protein kinase B
PI3K/AKT/mTOR pathway
Cell Proliferation
Wound Healing
Basic Sciences
Growth factor
Cell Cycle Checkpoints
HDAC6
medicine.disease
Cathepsins
Toll-Like Receptor 2
Histone Deacetylase Inhibitors
Disease Models, Animal
030104 developmental biology
Cancer research
Phosphatidylinositol 3-Kinase
Carotid Artery Injuries
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 15244636
- Volume :
- 36
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Accession number :
- edsair.doi.dedup.....8d812b7c61516847cb86c21fc07117ac