Cathepsin L promotes Vascular Intimal Hyperplasia after Arterial Injury.
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.
Center for Vascular Disease and Translational Medicine, the Third Xiangya Hospital, Central South University, Changsha, China.|Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh.|Department of Cardiology of the Third Xiangya Hospital, Central South University, Changsha, China.
Jingjing
J
Cai
Center for Vascular Disease and Translational Medicine, the Third Xiangya Hospital, Central South University, Changsha, China.|Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh.
Hua
H
Zhong
Center for Vascular Disease and Translational Medicine, the Third Xiangya Hospital, Central South University, Changsha, China.|Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh.
Jinze
J
Wu
Center for Vascular Disease and Translational Medicine, the Third Xiangya Hospital, Central South University, Changsha, China.
Rui-Fang
RF
Chen
The Feinstein Institute for Medical Research, Manhasset, New York.
Huan
H
Yang
The Feinstein Institute for Medical Research, Manhasset, New York.
Yousef
Y
Al-Abed
Center for Vascular Disease and Translational Medicine, the Third Xiangya Hospital, Central South University, Changsha, China.
Ying
Y
Li
Center for Vascular Disease and Translational Medicine, the Third Xiangya Hospital, Central South University, Changsha, China.
Xiaohui
X
Li
Department of Cardiology of the Third Xiangya Hospital, Central South University, Changsha, China.
Weihong
W
Jiang
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh.
Marcelo Freitas
MF
Montenegro
Center for Vascular Disease and Translational Medicine, the Third Xiangya Hospital, Central South University, Changsha, China.|Department of Cardiology of the Third Xiangya Hospital, Central South University, Changsha, China.
Hong
H
Yuan
Center for Vascular Disease and Translational Medicine, the Third Xiangya Hospital, Central South University, Changsha, China.|Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh.
Timothy
T
Billiar
Center for Vascular Disease and Translational Medicine, the Third Xiangya Hospital, Central South University, Changsha, China.|Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh.|Department of Cardiology of the Third Xiangya Hospital, Central South University, Changsha, China.
Alex F
AF
Chen
D000818:Animals; D020212:Carotid Artery Injuries / Q000188:drug therapy / Q000378:metabolism*; D056668:Cathepsin L / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006965:Hyperplasia / Q000188:drug therapy / Q000378:metabolism*; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D019258:Saquinavir / Q000627:therapeutic use; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D017539:Tunica Intima / Q000473:pathology*
D017320:HIV Protease Inhibitors; D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4; D056668:Cathepsin L; D019258:Saquinavir
Hyperplasisa; Monocytes; Toll-like Receptor 4; Vascular remodeling; cathepsin L/V