Abstract
The inflammatory pathways that drive the development of intimai 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.
Highlights
Endovascular interventions for arterial occlusive disease such as angioplasty and stent placement can fail due to restenosis
We show here that cathepsin L expression is markedly increased after carotid artery wire injury and that this depends on toll-like receptor 4 (TLR4)/myeloid differentiation primary response gene 88 (MyD88) signaling in myeloid cells
We had previously shown that global MyD88 deletion suppresses intimal hyperplasia [12], we show that myeloid-specific MyD88 deletion reduces intimal area, medial thickening and I/M ratio following wire injury to a level similar to that seen after TLR4 myeloid-specific knockout (Figures 2D, E, F and Supplementary Figure S3)
Summary
Endovascular interventions for arterial occlusive disease such as angioplasty and stent placement can fail due to restenosis These interventional procedures result in endothelial denudation with intimal and medial damage, which induces substantial local inflammation. This inflammation is manifested by monocyte infiltration as well as inflammatory mediator and growth factor production [1]. This in turn stimulates vascular smooth muscle cell (SMC) accumulation and extracellular matrix deposition, resulting in intimal hyperplasia (IH) and vessel or stent occlusion [2,3,4]. Since macrophage infiltration and activation are critical steps in the IH that follows acute injury to the arterial wall [12,13,14], we postulate that cathepsin L contributes to IH and that the TLR4MyD88 pathway in myeloid lineages regulates cathepsin L expression after wire injury
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