Experimental abdominal aortic aneurysm growth is inhibited by blocking the JAK2/STAT3 pathway
Experimental abdominal aortic aneurysm growth is inhibited by blocking the JAK2/STAT3 pathway
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DOI：
10.1016/j.ijcard.2020.03.072
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发表时间：
2020-08-01
影响因子：
3.5
通讯作者：
Liu, Jinping
中科院分区：
文献类型：
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作者：
Xiao, Jie;Wei, Zhanjie;Liu, Jinping
背景：JAK/STAT信号通路是一条重要的转录信号通路，调节基因表达和细胞活性。我们最近发表的研究强调了IL-17 A在腹主动脉瘤（AAA）形成和破裂中的作用。IL-17 A已被证明在一些疾病中上调血管内皮生长因子（VEGF）表达。但目前尚无研究证实JAK 2/STAT 3、IL-17 A和VEGF之间的关系。因此，我们假设IL-17 A可能通过JAK 2/STAT 3信号通路上调VEGF表达，从而放大炎症反应，加剧新生血管形成，加速AAA进展。方法：为了充分验证我们的假设，进行了两项独立的研究：i）一项研究调查JAK 2/STAT 3对AAA形成和进展的影响。ii）评估IL-17 A、JAK 2/STAT 3和VEGF之间的关系的研究。从7名接受开放手术的AAA患者和7名肝移植供体收集人体组织。对所有人主动脉组织进行组织学、免疫组化染色和Western blotting检测。结果：在人主动脉瘤组织中，JAK 2/STAT 3、IL-17 A和VEGF的表达水平均高于正常对照组。用WP1066（选择性JAK 2/STAT 3通路抑制剂）、IL-17 A和VEGF组治疗的组分别具有25%、40%和65%的AAA发生率，而对照组具有75%的发生率。组织学分析显示，IL-17 A和VEGF相关的炎症反应被WP 1066减弱。因此，用WP1066阻断JAK 2/STAT 3通路减弱了实验性AAA进展。此外，在研究ii中，我们发现IL-17 A siRNA似乎减弱了IL-17 A和VEGF的表达; VEGF siRNA治疗降低了VEGF的表达，而IL-17 A的表达仍然很高。结论：用JAK 2/STAT 3特异性抑制剂WP1066阻断JAK 2/STAT 3通路可减轻实验性AAA的进展。在AAA进展过程中，IL-17 A可能通过JAK 2/STAT 3信号通路影响VEGF的表达。这种潜在的机制可能为AAA的非手术治疗提供了一种新的策略。(c)2020年，任作家。由爱思唯尔公司出版。这是一篇开放获取的文章，使用CC BY-NC-ND许可证（http：//creativecommons.org/licenses/by-nc-nd/4.0/）。
Background: The JAK/STAT pathway is a vital transcription signaling pathway that regulates gene expression and cellular activity. Our recently published study highlighted the role of IL-17A in abdominal aortic aneurysm(AAA) formation and rupture. IL-17A has been proven to upregulate vascular endothelial growth factor (VEGF) expression in some diseases. However, no study has demonstrated the relationships among JAK2/STAT3, IL-17A and VEGF. Therefore, we hypothesized that IL-17A may up-regulate VEGF expression via the JAK2/STAT3 signaling pathway to amplify the inflammatory response, exacerbate neovascularization, and accelerate AAA progression.Methods: To fully verify our hypothesis, two separate studies were performed: i) a study investigating the influence of JAK2/STAT3 on AAA formation and progression. ii) a study evaluating the relationship among IL-17A, JAK2/STAT3 and VEGF. Human tissues were collected from 7 AAA patients who underwent open surgery and 7 liver transplantation donors. All human aortic tissues were examined by histological and immunohistochemical staining, andWestern blotting. Furthermore, mouse aortic tissues were also examined by histological and immunohistochemical staining and Western blotting, and the mouse aortic diameters were assessed by high resolution Vevo 2100 microimaging system.Results: Among human aortic tissues, JAK2/STAT3, IL-17A and VEGF expression levels were higher in AAA tissues than in control tissues. Group treated with WP1066 (a selective JAK2/STAT3 pathway inhibitor), IL-17A, and VEGF groups had AAA incidences of 25%, 40%, and 65%, respectively, while the control group had an incidence of 75%. Histopathological analysis revealed that the IL-17A- and VEGF-related inflammatory responses were attenuated byWP1066. Thus, blocking the JAK2/STAT3 pathway with WP1066 attenuated experimental AAA progression. In addition, in study ii, we found that IL-17A siRNA seemed to attenuate the expression of IL-17AandVEGF in vivo study; treatment with VEGF siRNA decreased the expression of VEGF, while IL-17Aexpressionremained high. Inaninvitrostudy, rhIL17A treatment increased JAK2/STAT3 and VEGF expression inmacrophages in a dose-dependent manner.Conclusion: Blocking the JAK2/STAT3 pathway with WP1066 (a JAK2/STAT3 specific inhibitor) attenuates experimental AAA progression. During AAA progression, IL-17A may influence the expression of VEGF via the JAK2/ STAT3 signaling pathway. This potential mechanism may suggest a novel strategy for nonsurgical AAA treatment. (c) 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).