Highly glycosylated CD147 promotes hemorrhagic transformation after rt-PA treatment in diabetes: a novel therapeutic target?
Highly glycosylated CD147 promotes hemorrhagic transformation after rt-PA treatment in diabetes: a novel therapeutic target?
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高度糖基化的 CD147 促进糖尿病 rt-PA 治疗后的出血转化：一个新的治疗靶点？
DOI：
10.1186/s12974-019-1460-1
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发表时间：
2019-04
影响因子：
9.3
通讯作者：
Cui Mei
中科院分区：
文献类型：
--
作者：
Xie Yanan;Wang Yingzhe;Ding Hongyan;Guo Min;Wang Xun;Dong Qiang;Cui Mei
背景糖尿病是重组组织型纤溶酶原激活剂（rt-PA）治疗后卒中后出血性转化的主要危险因素。然而，糖尿病加重出血性转化的机制尚不清楚。我们的目的是验证，CD 147，细胞外基质金属蛋白酶（MMP）诱导剂，发挥了至关重要的作用，在progress.MethodsWe进行大脑中动脉闭塞糖尿病和非糖尿病大鼠，有或无rt-PA治疗，然后比较的糖基化水平的CD 147，小窝蛋白-1，MMPs的活动，和血脑屏障（BBB）的通透性。在体外，衣霉素处理和遗传工具用于产生非糖基化和低糖基化的CD 147。内源性胰高血糖素样肽-1受体（GLP-1 R）激动剂被用来下调糖基化的CD 147在vivo.ResultsCompared非糖尿病大鼠，糖尿病大鼠表达更高水平的高糖基化的CD 147在内皮细胞和星形胶质细胞以下的rt-PA治疗伴随着更高的活性的基质金属蛋白酶和血脑屏障通透性，在大脑中动脉闭塞模型。Caveolin-1在糖尿病大鼠的星形胶质细胞和内皮细胞中也过表达并与CD 147共定位。在体外，晚期糖基化终产物增加了星形胶质细胞和内皮细胞中高度糖基化的CD 147的表达。下调CD 147的糖基化可降低MMPs的活性，促进紧密连接蛋白的表达。内皮细胞和星形胶质细胞中caveolin-1的表达不受衣霉素的抑制，表明caveolin-1位于CD 147的上游。结论CD 147在糖尿病相关rt-PA致出血性转化中起重要作用，下调CD 147糖基化可能是治疗糖尿病患者rt-PA治疗后神经血管单位修复的有效方法。
BackgroundDiabetes is known to be a main risk factor of post-stroke hemorrhagic transformation following recombinant tissue plasminogen activator (rt-PA) therapy. However, the mechanism through which diabetes exacerbates hemorrhagic transformation is insufficiently understood. We aimed to verify that CD147, the extracellular matrix metalloproteinase (MMP) inducer, played a vital role in the progress.MethodsWe performed middle cerebral artery occlusion on diabetic and non-diabetic rats, with or without rt-PA treatment, and then compared the glycosylation level of CD147, caveolin-1, MMPs activities, and blood-brain barrier (BBB) permeability. In vitro,tunicamycin treatment and genetic tools were used to produce non-glycosylated and lowly glycosylated CD147. An endogenous glucagon-like peptide-1 receptor (GLP-1R) agonist was used to downregulate the glycosylation of CD147 in vivo.ResultsCompared with non-diabetic rats, diabetic rats expressed higher levels of highly glycosylated CD147 in endothelium and astrocytes following rt-PA treatment accompanied by higher activity of MMPs and BBB permeability, in the middle cerebral artery occlusion model. Caveolin-1 was also overexpressed and co-localized with CD147 in astrocytes and endothelium in diabetic rats. In vitro, advanced glycation end products increased the expression of highly glycosylated CD147 in astrocytes and endothelial cells. Downregulating the glycosylation of CD147 lowered the activity of MMPs and promoted the expression of tight junction proteins. The expression of caveolin-1 in endothelial cells and astrocytes was not inhibited by tunicamycin, which revealed that caveolin-1 was an upstream of CD147. In vivo, GLP-1R agonist downregulated the glycosylation of CD147 and further reduced the activity of MMPs and protected the BBB in diabetic rats.ConclusionCD147 is essential for diabetes-associated rt-PA-induced hemorrhagic transformation, and downregulation of CD147 glycosylation is a promising therapy for neurovascular-unit repair after rt-PA treatment of patients with diabetes.
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影响因子：
8.3
作者：
Fan X;Qiu J;Yu Z;Dai H;Singhal AB;Lo EH;Wang X
通讯作者：
Wang X
影响因子：
14.6
作者：
Hill, MD;Buchan, AM
通讯作者：
Buchan, AM
DOI：
10.1016/s0140-6736(04)15692-4
发表时间：
2004-03
期刊：
The Lancet
影响因子：
--
作者：
W. Hacke;G. Donnan;C. Fieschi;M. Kaste;R. Kummer;J. Broderick;T. Brott;Michael R. Frankel;J. Grotta;E. Haley;T. Kwiatkowski;S. Levine;C. Lewandowski;M. Lu;P. Lyden;J. Marler;Suresh Patel;B. Tilley;G. Albers;E. Bluhmki;M. Wilhelm;S. Hamilton;Atlantis Trials Investigators;Ecass Trials Investigators
通讯作者：
W. Hacke;G. Donnan;C. Fieschi;M. Kaste;R. Kummer;J. Broderick;T. Brott;Michael R. Frankel;J. Grotta;E. Haley;T. Kwiatkowski;S. Levine;C. Lewandowski;M. Lu;P. Lyden;J. Marler;Suresh Patel;B. Tilley;G. Albers;E. Bluhmki;M. Wilhelm;S. Hamilton;Atlantis Trials Investigators;Ecass Trials Investigators
影响因子：
8.3
作者：
Fan X;Ning M;Lo EH;Wang X
通讯作者：
Wang X
DOI：
10.1016/j.biocel.2006.03.019
发表时间：
2006-01-01
影响因子：
4
作者：
Jia, Li;Wang, Hujing;Zhang, Jianing
通讯作者：
Zhang, Jianing