Dapsone protects brain microvascular integrity from high-fat diet induced LDL oxidation

Rui Zhan,Huan Yang,Xiaoda Yang,Bing Pan,Qihua He,Yining Huang,Ting Zhou,Tao Zhang,Weiwei Yu,Lei Zhao,Mingming Zhao,Dehua Chui,Belinda Willard,Hecheng Wang,Lemin Zheng,Yinglan Jin,Yingyu Chen,Yue Chen,Xiangyang Guo

doi:10.1038/s41419-018-0739-y

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.

Highlights

Atherosclerosis is understood to be a disease characterized by inflammation and oxidative stress that results in many vascular-related complications, including ischemia, acute coronary syndromes, and stroke[1]
We demonstrate that DDS protected brain microvascular integrity via its anti-oxidative role and reducing lysosome accumulation in a high-fat diet (HFD) mouse model that mimic human western diets, which indicate that DDS can design to be a novel therapeutic candidate in brain vascular-related disorders under metabolism disorders, such as stroke and Alzheimer’s disease
Result 1: DDS protects brain microvascular integrity in mice with HFD To determine whether DDS has protective effects on brain microvessels, we examined the cortical microvascular permeability for tetramethylrhodamine (TMR)dextran (40 kDa) with multiphoton microscopy in a live optical study

Summary

Introduction

Atherosclerosis is understood to be a disease characterized by inflammation and oxidative stress that results in many vascular-related complications, including ischemia, acute coronary syndromes (e.g., myocardial infarction), and stroke[1]. Lipid metabolism is regarded as a key factor in many vascular-related diseases. Especially low-density lipoprotein (LDL) oxidation is considered a key risk factor of atherosclerosis. Under pathological conditions, oxidized LDL (oxLDL), the oxidative modified form of LDL, leads to lysosomal accumulation[2,3]. Significantly high level of oxLDL is observed[4], which can induce leukocytes to release inflammatory factors. It leads to dysfunction and apoptosis of vascular endothelial cells

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Conclusion