Abstract

Atherosclerosis was considered to induce many vascular-related complications, such as acute myocardial infarction and stroke. Abnormal lipid metabolism and its peroxidation inducing blood–brain barrier (BBB) leakage were associated with the pre-clinical stage of stroke. Dapsone (DDS), an anti-inflammation and anti-oxidation drug, has been found to have protective effects on vascular. However, whether DDS has a protective role on brain microvessels during lipid oxidation had yet to be elucidated. We investigated brain microvascular integrity in a high-fat diet (HFD) mouse model. We designed this study to explore whether DDS had protective effects on brain microvessels under lipid oxidation and tried to explain the underlying mechanism. In our live optical study, we found that DDS significantly attenuated brain microvascular leakage through reducing serum oxidized low-density lipoprotein (oxLDL) in HFD mice (p < 0.001), and DDS significantly inhibited LDL oxidation in vitro (p < 0.001). Our study showed that DDS protected tight junction proteins: ZO-1 (p < 0.001), occludin (p < 0.01), claudin-5 (p < 0.05) of microvascular endothelial cells in vivo and in vitro. DDS reversed LAMP1 aggregation in cytoplasm, and decreased the destruction of tight junction protein: ZO-1 in vitro. We first revealed that DDS had a protective role on cerebral microvessels through preventing tight junction ZO-1 from abnormal degradation by autophagy and reducing lysosome accumulation. Our findings suggested the significance of DDS in protecting brain microvessels under lipid metabolic disorders, which revealed a novel potential therapeutic strategy in brain microvascular-related diseases.

Details

Title
Dapsone protects brain microvascular integrity from high-fat diet induced LDL oxidation
Author
Zhan, Rui 1 ; Zhao, Mingming 2 ; Zhou, Ting 3 ; Chen, Yue 2 ; Yu, Weiwei 4 ; Zhao, Lei 3 ; Zhang, Tao 3 ; Wang, Hecheng 3 ; Yang, Huan 3   VIAFID ORCID Logo  ; Jin, Yinglan 3 ; He, Qihua 5 ; Yang, Xiaoda 6 ; Guo, Xiangyang 7 ; Willard, Belinda 8 ; Pan, Bing 2 ; Huang, Yining 4 ; Chen, Yingyu 9 ; Chui, Dehua 10 ; Zheng, Lemin 2 

1  Neuroscience Research Institute and Department of Neurobiology, Key Laboratory for Neuroscience, Ministry of Education and Ministry of Public Health, Health Science Center, Peking University, Beijing, China; The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Health Science Center, Beijing, China 
2  The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Health Science Center, Beijing, China 
3  Neuroscience Research Institute and Department of Neurobiology, Key Laboratory for Neuroscience, Ministry of Education and Ministry of Public Health, Health Science Center, Peking University, Beijing, China 
4  Department of Neurology, The Institute of Small Vessel Disease of the Nervous System, Peking University First Hospital, Beijing, China 
5  Center of Medical and Health Analysis, Peking University, Beijing, China 
6  School of pharmaceutical sciences, Health Science Center, Peking University, Beijing, China 
7  Department of Anesthesiology, Peking University Third Hospital, Beijing, China 
8  Proteomics Laboratory, Cleveland Clinic, Cleveland, Ohio, USA 
9  Department of Immunology, School of Basic Medical Sciences, Key Laboratory of Medical Immunology, Ministry of Health, Health Science Center, Peking University, Beijing, China 
10  Neuroscience Research Institute and Department of Neurobiology, Key Laboratory for Neuroscience, Ministry of Education and Ministry of Public Health, Health Science Center, Peking University, Beijing, China; Beijing Key Laboratory of Magnetic Resonance Imaging Devices and Technology, Peking University Third Hospital, Beijing, China 
Pages
1-15
Publication year
2018
Publication date
Jun 2018
Publisher
Springer Nature B.V.
e-ISSN
20414889
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41419-018-0739-y
ProQuest document ID
2054155442
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.