Dapsone protects brain microvascular integrity from high-fat diet induced LDL oxidation.
Dapsone protects brain microvascular integrity from high-fat diet induced LDL oxidation.
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氨苯砜保护脑微血管完整性免受高脂肪饮食诱导的低密度脂蛋白氧化的影响
DOI：
10.1038/s41419-018-0739-y
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发表时间：
2018-06-07
影响因子：
9
通讯作者：
Zheng L
中科院分区：
文献类型：
--
作者：
Zhan R;Zhao M;Zhou T;Chen Y;Yu W;Zhao L;Zhang T;Wang H;Yang H;Jin Y;He Q;Yang X;Guo X;Willard B;Pan B;Huang Y;Chen Y;Chui D;Zheng L
动脉粥样硬化被认为会引起许多血管相关并发症，如急性心肌梗死和中风。脂质代谢异常及其过氧化反应导致血脑屏障（BBB）渗漏与脑卒中临床前阶段有关。氨苯砜（DDS）是一种抗炎、抗氧化药物，具有血管保护作用。然而，DDS是否在脂质氧化过程中对脑微血管具有保护作用尚未阐明。我们研究了高脂饮食（HFD）小鼠模型的脑微血管完整性。本研究旨在探讨DDS对脂质过氧化损伤下脑微血管的保护作用及其机制。在我们的活体光学研究中，我们发现DDS通过降低HFD小鼠血清氧化低密度脂蛋白（oxLDL）显著减少脑微血管渗漏（p <0.001），并且DDS在体外显著抑制LDL氧化（p <0.001）。结果表明，DDS对体内外微血管内皮细胞紧密连接蛋白ZO-1（p <0.001）、occludin（p <0.01）、claudin-5（p <0.05）均有保护作用。DDS在体外可逆转LAMP1在胞浆内的聚集，减少紧密连接蛋白ZO-1的破坏。我们首次发现DDS通过防止紧密连接ZO-1被自噬异常降解和减少溶酶体积聚对脑微血管具有保护作用。提示DDS对脂代谢紊乱时脑微血管的保护具有重要意义，为脑微血管相关疾病的治疗提供了新的思路。
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.
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影响因子：
5.3
作者：
Bandyopadhyay, Urmi;Kaushik, Susmita;Cuervo, Ana Maria
通讯作者：
Cuervo, Ana Maria
影响因子：
7.7
作者：
Li, Jian;Pfeffer, Suzanne R.
通讯作者：
Pfeffer, Suzanne R.
DOI：
10.1073/pnas.1005078107
发表时间：
2010-11-09
影响因子：
11.1
作者：
Cho, Sung Chun;Park, Moon Cheol;Lee, Junho
通讯作者：
Lee, Junho
影响因子：
4.8
作者：
Leeuwenburgh, C;Rasmussen, JE;Heinecke, JW
通讯作者：
Heinecke, JW
影响因子：
56.9
作者：
BROWN, MS;KOVANEN, PT;GOLDSTEIN, JL
通讯作者：
GOLDSTEIN, JL