INTERNATIONAL JOURNAL OF CARDIOLOGY | 卷:312 |
Experimental abdominal aortic aneurysm growth is inhibited by blocking the JAK2/STAT3 pathway | |
Article | |
Xiao, Jie1  Wei, Zhanjie2  Chen, Xing3  Chen, Weiqiang3  Zhang, Hua3  Yang, Chuanlei1  Shang, Yuqiang1  Liu, Jinping4  | |
[1] Huazhong Univ Sci & Technol, Cent Hosp Wuhan, Tongji Med Coll, Dept Cardiovasc Surg, Wuhan 430014, Hubei, Peoples R China | |
[2] Huazhong Univ Sci & Technol, Cent Hosp Wuhan, Tongji Med Coll, Dept Thyroid & Breast Surg, Wuhan 430014, Hubei, Peoples R China | |
[3] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Cardiovasc Surg, Wuhan 430022, Hubei, Peoples R China | |
[4] Wuhan Univ, Zhongnan Hosp, Dept Cardiovasc Surg, Donghu Rd 169, Wuhan 430071, Hubei, Peoples R China | |
关键词: Abdominal aortic aneurysm; JAK2/STAT3; WP1066; IL-17A; VEGF; Inflammation; | |
DOI : 10.1016/j.ijcard.2020.03.072 | |
来源: Elsevier | |
【 摘 要 】
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/).
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