Abstract 14035: Cathepsin S Activity Controls Injury-Related Vascular Repair in Mice via the TLR2-mediated p38MAPK and PI3K–Akt-pHDAC6 Signaling Pathway
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 deacetylases (HDAC6) is required in modulating the proliferation and migration of various types of cancer cells. Here we investigated the crosstalk 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 p38MAPK, Akt and HDAC6 and toll-like receptor 2 (TLR2) expression in ligated arteries. The genetic or pharmacological inhibition of CatS also alleviated the increased phosphorylation of p38MAPK, Akt and HDAC6 induced by platelet-derived growth factor BB (PDGF-BB) in cultured vascular smooth muscle cells (VSMCs), and p38MAPK inhibition and Akt inhibition decreased the phospho-HDAC6 levels. Moreover, genetic or pharmacological CatS inhibition caused decrease in the levels of the HDAC6 activity in VSMCs in response to PDGF-BB. The HDAC6 inhibitor tubastatin A downregulated PDGF-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. TLR2 silencing decreased the phosphorylation levels of p38MAPK, Akt and HDAC6 and VSMC migration and proliferation.
Conclusions: This is the first report detailing cross-interaction between TLR-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.
Author Disclosures: H. Wu: None. X. Cheng: None. L. Hu: None. A. Inoue: None. G. Shi: None. M. Kuzuya: None. T. Murohara: None.
- © 2016 by American Heart Association, Inc.