Elevated postischemic tissue injury and leukocyte-endothelial adhesive interactions in mice with global deficiency in caveolin-2: role of PAI-1.
Elevated postischemic tissue injury and leukocyte-endothelial adhesive interactions in mice with global deficiency in caveolin-2: role of PAI-1.
复制标题
Caveolin-2 全面缺乏的小鼠缺血后组织损伤和白细胞-内皮粘附相互作用升高：PAI-1 的作用。
DOI：
10.1152/ajpheart.00682.2020
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Sowa,Grzegorz
中科院分区：
文献类型：
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作者：
Liu,Yajun;Wang,Meifang;Wang,Derek;Fay,WilliamP;Korthuis,RonaldJ;Sowa,Grzegorz
缺血/再灌注（I/R）诱导的快速炎症，涉及激活白细胞-内皮细胞粘附相互作用和白细胞浸润到组织中是缺血后组织损伤的主要因素。然而，参与这一病理过程的分子介质还不完全清楚。我们以前曾报道，小窝蛋白-2（Cav-2），质膜小窝的蛋白组分，调节小鼠肺癌肿瘤中的白细胞浸润。本研究的目的是检查Cav-2是否在I/R损伤和相关的急性白细胞介导的炎症中起作用。使用小鼠小肠I/R模型，我们证明了I/R下调小肠中Cav-2蛋白水平。使用Cav-2缺陷小鼠的进一步研究揭示了通过H& E染色组织切片中绒毛长度的评分确定的加重的缺血后组织损伤，其与通过IHC染色确定的MPO阳性组织浸润性白细胞的数量增加相关。活体显微镜分析的上游事件相对于白细胞的迁移和组织浸润显示，白细胞-内皮细胞粘附在毛细血管后微静脉，即白细胞滚动和粘附的相互作用也增强了Cav-2缺陷小鼠。从机制上讲，Cav-2缺陷增加了肠组织中纤溶酶原激活物抑制剂-1（派-1）蛋白水平，并且派-1的药理学抑制对Cav-2缺陷小鼠中I/R组织损伤加重和毛细血管后微静脉中白细胞-内皮细胞相互作用增强具有总体更大的抑制作用。总之，我们的数据表明，Cav-2蛋白通过抑制派-1蛋白水平，从而减少白细胞-内皮细胞粘附interactions.NEW和值得注意的是，caveolin-2在调节缺血/再灌注（I/R）组织损伤和其影响的机制是未知的组织损伤。本研究采用Caveolin-2缺陷小鼠和小肠I/R损伤模型，研究Caveolin-2在白细胞依赖性再灌注损伤中的作用。我们首次证明小窝蛋白-2通过降低肠组织中派-1蛋白水平和毛细血管后微静脉中白细胞-内皮粘附相互作用，对I/R诱导的白细胞依赖性再灌注损伤起保护作用。
Ischemia/reperfusion (I/R)-induced rapid inflammation involving activation of leukocyte-endothelial adhesive interactions and leukocyte infiltration into tissues is a major contributor to postischemic tissue injury. However, the molecular mediators involved in this pathological process are not fully known. We have previously reported that caveolin-2 (Cav-2), a protein component of plasma membrane caveolae, regulated leukocyte infiltration in mouse lung carcinoma tumors. The goal of the current study was to examine if Cav-2 plays a role in I/R injury and associated acute leukocyte-mediated inflammation. Using a mouse small intestinal I/R model, we demonstrated that I/R downregulates Cav-2 protein levels in the small bowel. Further study using Cav-2-deficient mice revealed aggravated postischemic tissue injury determined by scoring of villi length in H&E-stained tissue sections, which correlated with increased numbers of MPO-positive tissue-infiltrating leukocytes determined by IHC staining. Intravital microscopic analysis of upstream events relative to leukocyte transmigration and tissue infiltration revealed that leukocyte-endothelial cell adhesive interactions in postcapillary venules, namely leukocyte rolling and adhesion were also enhanced in Cav-2-deficient mice. Mechanistically, Cav-2 deficiency increased plasminogen activator inhibitor-1 (PAI-1) protein levels in the intestinal tissue and a pharmacological inhibition of PAI-1 had overall greater inhibitory effect on both aggravated I/R tissue injury and enhanced leukocyte-endothelial interactions in postcapillary venules in Cav-2-deficient mice. In conclusion, our data suggest that Cav-2 protein alleviates tissue injury in response to I/R by dampening PAI-1 protein levels and thereby reducing leukocyte-endothelial adhesive interactions.NEW & NOTEWORTHYThe role of caveolin-2 in regulating ischemia/reperfusion (I/R) tissue injury and the mechanisms underlying its effects are unknown. This study uses caveolin-2-deficient mouse and small intestinal I/R injury models to examine the role of caveolin-2 in the leukocyte-dependent reperfusion injury. We demonstrate for the first time that caveolin-2 plays a protective role from the I/R-induced leukocyte-dependent reperfusion injury by reducing PAI-1 protein levels in intestinal tissue and leukocyte-endothelial adhesive interactions in postcapillary venules.