Cathepsin L promotes Vascular Intimal Hyperplasia after Arterial Injury

• Published in: Molecular medicine (Cambridge, Mass.) Mass.), 2017-01, Vol.23 (1), p.92-100
• Main Authors: Cai, Jingjing, Zhong, Hua, Wu, Jinze, Chen, Rui-Fang, Yang, Huan, Al-Abed, Yousef, Li, Ying, Li, Xiaohui, Jiang, Weihong, Montenegro, Marcelo Freitas, Yuan, Hong, Billiar, Timothy, Chen, Alex F
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Carotid arteries; Carotid Artery Injuries - drug therapy; Carotid Artery Injuries - metabolism; Cathepsin L - genetics; Cathepsin L - metabolism; Cell adhesion & migration; Cells, Cultured; Extracellular matrix; FDA approval; HIV Protease Inhibitors - therapeutic use; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - physiology; Humans; Hyperplasia; Hyperplasia - drug therapy; Hyperplasia - metabolism; Infrared imaging systems; Mice, Knockout; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Proteins; Saquinavir - therapeutic use; Smooth muscle; Software; Surgery; Toll-Like Receptor 4 - metabolism; Tunica Intima - pathology; Veins & arteries
• ISSN: 1076-1551; 1528-3658; 1528-3658
• DOI: 10.2119/molmed.2016.00222

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 day 7 and remains elevated to 28 days. The 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 a 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 FDA approved drug, SQV blocks IH though mechanisms that may include the suppression of cathepsin L.