Advanced glycation end products induce endothelial hyperpermeability via β-catenin phosphorylation and subsequent up-regulation of ADAM10.
Advanced glycation end products induce endothelial hyperpermeability via β-catenin phosphorylation and subsequent up-regulation of ADAM10.
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晚期糖基化终末产物通过 β-连环蛋白磷酸化和随后 ADAM10 的上调诱导内皮细胞通透性过高
DOI：
10.1111/jcmm.16659
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发表时间：
2021-08
影响因子：
5.3
通讯作者：
Guo X
中科院分区：
文献类型：
--
作者：
Weng J;Chen Z;Li J;He Q;Chen D;Yang L;Su H;Huang J;Yu S;Huang Q;Xu Q;Guo X
内皮细胞通透性增高是糖尿病微血管并发症发生的起始事件，晚期糖基化终产物（AGEs）被认为是糖尿病内皮细胞通透性增高的主要原因，但其分子机制尚不清楚。据报道，β-连环蛋白通过充当粘附组分和信号转导组分在维持正常内皮渗透性方面发挥双重功能。在这里，我们发现AGEs诱导β-catenin在残基Y 654和Y142处的磷酸化，并且当这两个残基被阻断时，内皮高通透性被逆转。在机制上，Y 654的磷酸化被Src失活阻断，而Y142的磷酸化被粘着斑激酶抑制剂降低。AGEs诱导的β-catenin Y 654磷酸化促进血管内皮（VE）-cadherin/β-catenin的解离和粘附连接（AJs）的损伤，而β-catenin Y142磷酸化促进β-catenin和α-catenin的解离。进一步的研究表明，β-catenin Y142磷酸化是AGEs介导的β-catenin核转位所必需的，这种核定位的β-catenin随后激活了TCF/LEF通路。该途径促进Wnt靶点ADAM 10（一种解整合素和金属蛋白酶10）的转录，其介导VE‐钙粘蛋白脱落并导致AJs的进一步损伤。总之，我们的研究显示了β-catenin Y 654和Y142磷酸化通过VE-cadherin/β-catenin/α-catenin解离和ADAM 10上调在AGEs介导的内皮细胞通透性增高中的作用，从而促进了我们对AGEs诱导的微血管通透性增高的潜在机制的理解。
Endothelial hyperpermeability is the initial event in the development of diabetic microvascular complications, and advanced glycation end products (AGEs) are suggested to cause much of the endothelial hyperpermeability associated with diabetes mellitus, but the molecular mechanism remains to be characterized. β‐catenin reportedly plays dual functions in maintaining normal endothelial permeability by serving both as an adhesive component and a signal transduction component. Here, we found that AGEs induced the phosphorylation of β‐catenin at residues Y654 and Y142 and the endothelial hyperpermeability was reversed when the two residues were blocked. In mechanism, phosphorylation of Y654 was blocked by Src inactivation, whereas phosphorylation of Y142 was reduced by a focal adhesion kinase inhibitor. β‐catenin Y654 phosphorylation induced by AGEs facilitated the dissociation of vascular endothelial (VE)‐cadherin/β‐catenin and the impairment of adherens junctions (AJs), whereas β‐catenin Y142 phosphorylation favoured the dissociation of β‐catenin and α‐catenin. Further investigation revealed that β‐catenin Y142 phosphorylation was required for AGEs‐mediated β‐catenin nuclear translocation, and this nuclear‐located β‐catenin subsequently activated the TCF/LEF pathway. This pathway promotes the transcription of the Wnt target, ADAM10 (a disintegrin and metalloprotease 10), which mediates VE‐cadherin shedding and leads to further impairment of AJs. In summary, our study showed the role of β‐catenin Y654 and Y142 phosphorylation in AGEs‐mediated endothelial hyperpermeability through VE‐cadherin/β‐catenin/α‐catenin dissociation and up‐regulation of ADAM10, thereby advancing our understanding of the underlying mechanisms of AGEs‐induced microvascular hyperpermeability.
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影响因子：
64.5
作者：
Drees, F;Pokutta, S;Weis, WI
通讯作者：
Weis, WI
DOI：
10.1073/pnas.1323761111
发表时间：
2014-02-04
影响因子：
11.1
作者：
Chang, Shun-Fu;Chen, Li-Jing;Chiu, Jeng-Jiann
通讯作者：
Chiu, Jeng-Jiann
DOI：
10.1083/jcb.201706013
发表时间：
2018-03-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gayrard C;Bernaudin C;Déjardin T;Seiler C;Borghi N
通讯作者：
Borghi N
影响因子：
3.6
作者：
Kim, M. P.;Park, S. I.;Kopetz, S.;Gallick, G. E.
通讯作者：
Gallick, G. E.
影响因子：
11.8
作者：
Corada M;Nyqvist D;Orsenigo F;Caprini A;Giampietro C;Taketo MM;Iruela-Arispe ML;Adams RH;Dejana E
通讯作者：
Dejana E