Cathepsin L Promotes Vascular Intimal Hyperplasia after Arterial Injury

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
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.
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Date Published
March 20, 2017
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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