Original articles
Jingshu Tang, Yuying Kang, Longjian Huang, Lei Wu, Ying Penga. TIMP1 preserves the blood-brain barrier through interacting with CD63/integrin β1 complex and regulating downstream FAK/RhoA signaling[J]. Acta Pharmaceutica Sinica B, 2020, 10(6): 987-1003

TIMP1 preserves the blood-brain barrier through interacting with CD63/integrin β1 complex and regulating downstream FAK/RhoA signaling
Jingshu Tang, Yuying Kang, Longjian Huang, Lei Wu, Ying Penga
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Abstract:
Blood-brain barrier (BBB) breakdown and the associated microvascular hyperpermeability are hallmark features of several neurological disorders, including traumatic brain injury (TBI). However, there is no viable therapeutic strategy to rescue BBB function. Tissue inhibitor of metalloproteinase-1 (TIMP1) has been considered to be beneficial for vascular integrity, but the molecular mechanisms underlying the functions of TIMP1 remain elusive. Here, we report that TIMP1 executes a protective role on neuroprotective function via ameliorating BBB disruption in mice with experimental TBI. In human brain microvessel endothelial cells (HBMECs) exposed to hypoxia and inflammation injury, the recombinant TIMP1 (rTIMP1) treatment maintained integrity of junctional proteins and trans-endothelial tightness. Mechanistically, TIMP1 interacts with CD63/integrin β1 complex and activates downstream FAK signaling, leading to attenuation of RhoA activation and F-actin depolymerization for endothelial cells structure stabilization. Notably, these effects depend on CD63/integrin β1 complex, instead of the MMP-inhibitory function. Together, our results identified a novel MMP-independent function of TIMP1 in regulating endothelial barrier integrity. Therapeutic interventions targeting TIMP1 and its downstream signaling may be beneficial to protect BBB function following brain injury and neurological disorders.
Key words:    issue inhibitor of metalloproteinase-1    Blood-brain barrier    Junctional proteins    CD63    Integrin β1   
Received: 2019-12-25     Revised: 2020-01-22
DOI: 10.1016/j.apsb.2020.02.015
Funds: This project was supported by the grants from National Natural Science Foundation of China (Nos. 81872855 and 81673420), CAMS Innovation Fund for Medical Sciences (No. 2017-I2M-2-004, China), National Science and Technology Major Project on Major New Drug Innovation of China (2018ZX09711001-003-005 and 2018ZX09711001-003-009), Fundamental Research Funds for the Central Universities (3332019070, China) and Disciplines construction project (20190200802, China).
Corresponding author: Ying Peng     Email:ypeng@imm.ac.cn
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Jingshu Tang
Yuying Kang
Longjian Huang
Lei Wu
Ying Penga

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