Oxidative Stress Product, 4-Hydroxy-2-Nonenal, Induces the Release of Tissue Factor-Positive Microvesicles From Perivascular Cells Into Circulation.
Oxidative Stress Product, 4-Hydroxy-2-Nonenal, Induces the Release of Tissue Factor-Positive Microvesicles From Perivascular Cells Into Circulation.
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DOI：
10.1161/atvbaha.120.315187
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Rao LVM
中科院分区：
文献类型：
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作者：
Ansari SA;Keshava S;Pendurthi UR;Rao LVM
补充数字内容可在文本中找到。组织因子（TF）在止血中起关键作用，但TF的异常表达导致血栓形成。本研究的目的是研究4-羟基-2-壬烯醛（HNE），在各种疾病条件下产生的最稳定和主要的氧化剂，对TF+微泡释放到循环中的影响，确定TF+微泡的来源，并评估其对血管内凝血和炎症的影响。C57 BL/6 J小鼠腹腔内施用HNE，并使用凝血测定和纳米颗粒追踪分析评估TF+微泡释放到循环中。使用各种细胞特异性标志物来鉴定TF+微泡的细胞来源。通过伊文思蓝染料或荧光素葡聚糖外渗分析血管通透性。对小鼠施用HNE显著增加了循环中TF+微泡和凝血酶生成的水平。HNE给药还增加了肺中嗜中性粒细胞的数量，并升高了血浆中炎性细胞因子的水平。施用抗TF抗体不仅阻断HNE诱导的凝血酶生成，而且阻断HNE诱导的炎症。共聚焦显微镜和免疫印迹研究表明，HNE不诱导TF表达无论是在血管内皮细胞或循环单核细胞。从给予HNE的小鼠中收获的微囊泡用CD 248和α-平滑肌肌动蛋白（血管周围细胞特异性标志物）染色呈阳性。发现HNE使内皮细胞屏障完整性不稳定。HNE促进TF+微泡从血管周围细胞释放到循环中。HNE诱导的TF活性增加有助于血管内凝血和炎症。
Supplemental Digital Content is available in the text. TF (Tissue factor) plays a key role in hemostasis, but an aberrant expression of TF leads to thrombosis. The objective of the present study is to investigate the effect of 4-hydroxy-2-nonenal (HNE), the most stable and major oxidant produced in various disease conditions, on the release of TF+ microvesicles into the circulation, identify the source of TF+ microvesicles origin, and assess their effect on intravascular coagulation and inflammation. C57BL/6J mice were administered with HNE intraperitoneally, and the release of TF+ microvesicles into circulation was evaluated using coagulation assays and nanoparticle tracking analysis. Various cell-specific markers were used to identify the cellular source of TF+ microvesicles. Vascular permeability was analyzed by the extravasation of Evans blue dye or fluorescein dextran. HNE administration to mice markedly increased the levels of TF+ microvesicles and thrombin generation in the circulation. HNE administration also increased the number of neutrophils in the lungs and elevated the levels of inflammatory cytokines in plasma. Administration of an anti-TF antibody blocked not only HNE-induced thrombin generation but also HNE-induced inflammation. Confocal microscopy and immunoblotting studies showed that HNE does not induce TF expression either in vascular endothelium or circulating monocytes. Microvesicles harvested from HNE-administered mice stained positively with CD248 and α-smooth muscle actin, the markers that are specific to perivascular cells. HNE was found to destabilize endothelial cell barrier integrity. HNE promotes the release of TF+ microvesicles from perivascular cells into the circulation. HNE-induced increased TF activity contributes to intravascular coagulation and inflammation.