Neutrophil Elastase Increases Vascular Permeability and Leukocyte Transmigration in Cultured Endothelial Cells and Obese Mice.
Neutrophil Elastase Increases Vascular Permeability and Leukocyte Transmigration in Cultured Endothelial Cells and Obese Mice.
复制标题
DOI：
10.3390/cells11152288
复制
发表时间：
2022-07-25
期刊：
影响因子：
6
通讯作者：
Jiang, Zhen Y.
中科院分区：
文献类型：
--
作者：
Ushakumari, Chinchu Jagadan;Zhou, Qiong L.;Wang, Yu-Hua;Na, Sijia;Rigor, Michael C.;Zhou, Cindy Y.;Kroll, Max K.;Lin, Benjamin D.;Jiang, Zhen Y.
中性粒细胞弹性蛋白酶(NE)在炎症中起着关键作用。然而，NE介导的炎症在肥胖中的机制仍不清楚。在此，我们报道了去甲肾上腺素激活蛋白酶激活受体-2(PAR2)，刺激肌动蛋白细丝(F-肌动蛋白)的形成，减少细胞间连接分子VE-钙粘蛋白的表达，增加人动脉内皮细胞(HECS)的通透性。NE还通过对MG132敏感的蛋白酶体促进VE-钙粘蛋白及其结合蛋白p120和β-连环蛋白的降解。NE刺激肌球蛋白轻链(MLC)及其调节因子肌球蛋白磷酸酶靶向亚单位-1(MYPT1)的磷酸化，MYPT1是Rho激酶(ROCK)的靶标。PAR2和ROCK的抑制剂可抑制NE诱导的HEC中F-肌动蛋白的形成、MLC的磷酸化和VE-钙粘蛋白的还原，并阻止单核细胞通过中性粒细胞或NE处理的HEC单层迁移。此外，给予NE抑制剂GW311616A显著减少高脂饮食(HFD)诱导的肥胖小鼠白色脂肪组织中的血管渗漏、白细胞渗透和促炎细胞因子的表达。同样，NE缺乏的小鼠对HFD诱导的心脏血管渗漏具有抵抗力。总而言之，NE通过激活内皮细胞中的PAR2信号来调节肌动蛋白细胞骨架活性和VE-钙粘蛋白的表达，导致血管通透性增加和白细胞渗出。因此，抑制去甲肾上腺素是减轻肥胖相关全身炎症中血管损伤和白细胞渗透的潜在方法。
Neutrophil elastase (NE) plays a pivotal role in inflammation. However, the mechanism underlying NE-mediated inflammation in obesity remains unclear. Here, we report that NE activates protease-activated receptor-2 (PAR2), stimulates actin filament (F-actin) formation, decreases intercellular junction molecule VE-cadherin expression, and increases the permeability of human arterial endothelial cells (hECs). NE also prompts degradation of VE-cadherin and its binding proteins p120- and β-catenins via MG132-sensitive proteasomes. NE stimulates phosphorylation of myosin light-chain (MLC) and its regulator myosin phosphatase target subunit-1 (MYPT1), a target of Rho kinase (ROCK). Inhibitors of PAR2 and ROCK prohibit NE-induced F-actin formation, MLC phosphorylation, and VE-cadherin reduction in hECs, and impede monocyte transmigration through hEC monolayer pretreated with either neutrophils or NE. Further, administration of an NE inhibitor GW311616A significantly attenuates vascular leakage, leukocyte infiltration, and the expression of proinflammatory cytokines in the white adipose tissue from high-fat diet (HFD)-induced obese mice. Likewise, NE-deficient mice are resistant to HFD-induced vascular leakage in the heart. Together, NE regulates actomyosin cytoskeleton activity and VE-cadherin expression by activating PAR2 signaling in the endothelial cells, leading to increased vascular permeability and leukocyte extravasation. Hence, inhibition of NE is a potential approach to mitigate vascular injury and leukocyte infiltration in obesity-related systemic inflammation.
登录
查看更多内容
影响因子：
2.9
作者：
Amano, Mutsuki;Nakayama, Masanori;Kaibuchi, Kozo
通讯作者：
Kaibuchi, Kozo
DOI：
10.1186/1478-811x-11-37
发表时间：
2013-05-28
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Hebda JK;Leclair HM;Azzi S;Roussel C;Scott MG;Bidère N;Gavard J
通讯作者：
Gavard J
影响因子：
20.1
作者：
Klarenbach, SW;Chipiuk, A;Murray, AG
通讯作者：
Murray, AG
DOI：
10.1007/978-1-62703-845-4_3
发表时间：
2014
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Siemsen DW;Malachowa N;Schepetkin IA;Whitney AR;Kirpotina LN;Lei B;Deleo FR;Quinn MT
通讯作者：
Quinn MT
肿瘤坏死因子-α的脂肪表达--在与肥胖相关的胰岛素抵抗中的直接作用
影响因子：
56.9
作者：
HOTAMISLIGIL, GS;SHARGILL, NS;SPIEGELMAN, BM
通讯作者：
SPIEGELMAN, BM