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Molecular Medicine

, Volume 23, Issue 1, pp 92–100 | Cite as

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
  • Alex F. Chen
Research Article

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.

Notes

Acknowledgments

This work was supported in part by the National Basic Research Program (973 Program) of China, 2014CB542400 (to AFC); the National Science Foundation of China, 81370359 and 91339204 (to AFC), 81570271 (to JJC) and 81273594 and 81470535 (to HY), and the National Institutes of Health, R01 GM50441 (to TRB).

Supplementary material

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Supplementary material, approximately 1.58 MB.

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Authors and Affiliations

  • Jingjing Cai
    • 1
    • 2
    • 3
  • Hua Zhong
    • 1
    • 2
  • Jinze Wu
    • 1
    • 2
  • Rui-Fang Chen
    • 1
  • Huan Yang
    • 4
  • Yousef Al-Abed
    • 4
  • Ying Li
    • 1
  • Xiaohui Li
    • 1
  • Weihong Jiang
    • 3
  • Marcelo F. Montenegro
    • 2
  • Hong Yuan
    • 1
    • 3
  • Timothy R. Billiar
    • 1
    • 2
    • 5
  • Alex F. Chen
    • 1
    • 2
    • 3
  1. 1.Center for Vascular Disease and Translational Medicine, Third Xiangya HospitalCentral South UniversityChangshaChina
  2. 2.W939 Biomedical Science Tower, Department of SurgeryUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.Department of Cardiology, Third Xiangya HospitalCentral South UniversityChangshaChina
  4. 4.The Feinstein Institute for Medical ResearchManhassetUSA
  5. 5.UPMC Presbyterian HospitalPittsburghUSA

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