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Cathepsin L promotes Vascular Intimal Hyperplasia after Arterial Injury.

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 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.

SUBMITTER: Cai J

PROVIDER: S-EPMC5468173 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Cathepsin L promotes Vascular Intimal Hyperplasia after Arterial Injury.

Cai Jingjing J Zhong Hua H Wu Jinze J Chen Rui-Fang RF Yang Huan H Al-Abed Yousef Y Li Ying Y Li Xiaohui X Jiang Weihong W Montenegro Marcelo Freitas MF Yuan Hong H Billiar Timothy T Chen Alex F AF

Molecular medicine (Cambridge, Mass.) 20160320

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 inju ...[more]

PMID: 28332696

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Project description:BACKGROUND AND OBJECTIVES:Preoperative arterial function is associated with arteriovenous fistula (AVF) development. Because arterial pathology may correlate with its function, preexisting arterial intimal hyperplasia may be associated with AVF development. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Vascular specimens obtained from 125 patients (with minimal 2 mm arterial diameter and 2.5 mm venous diameter) undergoing AVF creation were quantified for arterial intimal hyperplasia, arterial medial fibrosis, arterial microcalcification, and venous intimal hyperplasia. A 6-week postoperative ultrasound quantified AVF diameter, blood flow, and stenosis. Clinical AVF maturation was assessed using a predefined protocol. In a prospective cohort study design, we investigated the association of preexisting arterial intimal hyperplasia with the postoperative AVF diameter, blood flow, stenosis, and clinical maturation failure, after controlling for baseline demographics, comorbidities, and preoperative vein diameter. Additional analyses evaluated whether other vascular pathologies interacted with arterial intimal hyperplasia in affecting AVF outcomes. RESULTS:The median intimal thickness of the native artery was 22.0 μm (interquartile range, 14.8-37.1 μm). The median postoperative AVF diameter was 4.8 (interquartile range, 3.7-6.8) mm, blood flow was 796 (interquartile range, 413-1036) ml/min, and stenosis was present in 37 out of 98 patients with ultrasound data (38%). AVF nonmaturation occurred in 37 out of 125 patients (30%). Preexisting arterial intimal thickness was not significantly associated with AVF blood flow (-12 ml/min; 95% confidence interval [95% CI], -55 to 30 ml/min), diameter (-0.04 mm; 95% CI, -0.21 to 0.14 mm), stenosis (odds ratio, 0.93; 95% CI, 0.75 to 1.14), or clinical maturation failure (odds ratio, 1.07; 95% CI, 0.90 to 1.28), all per 10 μm increase. There was no significant interaction of preexisting arterial intimal thickness and postoperative AVF outcomes with arterial medial fibrosis, arterial microcalcification, or venous intimal hyperplasia. CONCLUSIONS:Preexisting arterial intimal hyperplasia is not associated with the 6-week AVF blood flow, diameter or stenosis, or clinical maturation when the preoperative arterial diameter is ≥2 mm.

Dataset Information

Cathepsin L promotes Vascular Intimal Hyperplasia after Arterial Injury.

Publications

Cathepsin L promotes Vascular Intimal Hyperplasia after Arterial Injury.

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