Oxidative stress-induced MMP- and γ-secretase-dependent VE-cadherin processing is modulated by the proteasome and BMP9/10.
Oxidative stress-induced MMP- and γ-secretase-dependent VE-cadherin processing is modulated by the proteasome and BMP9/10.
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DOI：
10.1038/s41598-022-27308-2
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发表时间：
2023-01-11
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
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经典的钙粘蛋白，包括血管内皮(VE)-钙粘蛋白，是基质金属蛋白酶（MMPs）和γ-分泌酶在粘附连接（AJ）分解过程中的靶标，这一机制可能与内皮细胞（EC）完整性和血管稳态有关。在这里，我们发现H2O2暴露引发的氧化应激诱导MMPs和γ-分泌酶在人脐内皮细胞（HUVECs）中有效地水解ve -钙粘蛋白。由γ-分泌酶产生的VE-cadherin的细胞质结构域VE-Cad/ ctf2是一个迄今为止无法识别的片段，在H2O2处理后可以很容易地检测到。释放到细胞质中的VE-Cad/CTF2受到蛋白酶体降解的严格调控，由adam10 /17生成的c端片段VE-Cad/CTF1依次产生。有趣的是，BMP9和BMP10这两种循环配体在血管维持中起着至关重要的作用，在H2O2胁迫下显著降低VE-Cad/CTF2水平，并在ve -钙粘蛋白加工过程中减轻H2O2介导的肌动蛋白细胞骨架分解。值得注意的是，BMP9/10预处理能有效减少H2O2诱导的细胞凋亡，有利于内皮细胞的恢复。因此，氧化应激是MMP-和γ-分泌酶介导的内皮细胞ve -钙粘蛋白和AJ从细胞骨架上分解的触发机制，这一机制由内皮细胞静止因子BMP9和BMP10负向控制。
Classical cadherins, including vascular endothelial (VE)-cadherin, are targeted by matrix metalloproteinases (MMPs) and γ-secretase during adherens junction (AJ) disassembly, a mechanism that might have relevance for endothelial cell (EC) integrity and vascular homeostasis. Here, we show that oxidative stress triggered by H2O2 exposure induced efficient VE-cadherin proteolysis by MMPs and γ-secretase in human umbilical endothelial cells (HUVECs). The cytoplasmic domain of VE-cadherin produced by γ-secretase, VE-Cad/CTF2—a fragment that has eluded identification so far—could readily be detected after H2O2 treatment. VE-Cad/CTF2, released into the cytosol, was tightly regulated by proteasomal degradation and was sequentially produced from an ADAM10/17-generated C-terminal fragment, VE-Cad/CTF1. Interestingly, BMP9 and BMP10, two circulating ligands critically involved in vascular maintenance, significantly reduced VE-Cad/CTF2 levels during H2O2 challenge, as well as mitigated H2O2-mediated actin cytoskeleton disassembly during VE-cadherin processing. Notably, BMP9/10 pretreatments efficiently reduced apoptosis induced by H2O2, favoring endothelial cell recovery. Thus, oxidative stress is a trigger of MMP- and γ-secretase-mediated endoproteolysis of VE-cadherin and AJ disassembly from the cytoskeleton in ECs, a mechanism that is negatively controlled by the EC quiescence factors, BMP9 and BMP10.
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影响因子：
5.3
作者：
Jacob, Kimberly D.;Noren Hooten, Nicole;Trzeciak, Andrzej R.;Evans, Michele K.
通讯作者：
Evans, Michele K.
影响因子：
4
作者：
Dejana, Elisabetta;Orsenigo, Fabrizio;Lampugnani, Maria Grazia
通讯作者：
Lampugnani, Maria Grazia
影响因子：
5.5
作者：
Chatterjee, Prodyot K.;Al-Abed, Yousef;Metz, Christine N.
通讯作者：
Metz, Christine N.
影响因子：
7.4
作者：
López-Ongil, S;Torrecillas, G;Rodríguez-Puyol, D
通讯作者：
Rodríguez-Puyol, D
DOI：
10.1073/pnas.96.17.9815
发表时间：
1999-08-17
影响因子：
11.1
作者：
Corada, M;Mariotti, M;Dejana, E
通讯作者：
Dejana, E