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Cathepsin L Promotes Vascular Intimal Hyperplasia after Arterial Injury

Authors
Jingjing Cai, Hua Zhong, Jinze Wu, Rui-Fang Chen, Huan Yang, Yousef Al-Abed, Ying Li,Xiaohui Li, Weihong Jiang, Marcelo F Montenegro, Hong Yuan, Timothy R Billiar, and Alex F Chen
Abstract
The inflammatory pathways that drive the development of intimal hyperplasia (IH) following arterial injury are not fully understood. We hypothesized that the lysosomal cysteine protease cathepsin L activates processes leading to IH after arterial injury. Using a mouse model of wire-induced carotid artery injury, we showed that cathepsin L activity peaks at d 7 and remains elevated for 28 d. Genetic deletion of cathepsin L prevented IH and monocyte recruitment in the carotid wall. The injury-induced increases in cathepsin L mRNA and activity were mitigated in mice with myeloid-specific deletion of toll-like receptor 4 (TLR4) or myeloid differentiation primary response gene 88 (MyD88). We further discovered that the HIV protease inhibitor saquinavir (SQV), which is known to block recombinant mouse cathepsin L activity in vitro, prevented IH after arterial injury. SQV also suppressed LPS (TLR4 agonist)–induced monocyte adhesion to endothelial monolayers. These findings establish cathepsin L as a critical regulator of the inflammation that leads to IH and that the TLR4-MyD88 pathway in myeloid lineages regulates cathepsin L expression in the vessel wall following wire injury. The Food and Drug Administration–approved drug SQV blocks IH though mechanisms that may include the suppression of cathepsin L.
Volume
2017
Page Range
92-100
DOI
10.2119/molmed.2016.00222
Date Published
March 20, 2017
Article PDF
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Supplemental Data
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Keywords
Cai, Zhong, Wu, Chen, Yang, Al-Abed, Li, Jiang, Montenegro, Yuan, Billiar, cathepsin L, lysosomal cysteine protease, arterial injury, inflammation, intimal hyperplasia, IH, arterial occlusive disease, cathepsins, saquinavir, SQV
Article Type
Research Article