Elsevier

International Journal of Cardiology

Volume 312, 1 August 2020, Pages 100-106
International Journal of Cardiology

Experimental abdominal aortic aneurysm growth is inhibited by blocking the JAK2/STAT3 pathway

https://doi.org/10.1016/j.ijcard.2020.03.072Get rights and content
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Highlights

  • JAK2/STAT3 pathway plays a crucial role in the progression of experimental abdominal aortic aneurysm.

  • Blocking the JAK2/STAT3 pathway with WP1066 (a JAK2/STAT3 specific inhibitor) can attenuates experimental AAA progression.

  • IL-17A and VEGF plays an important roles in the inflammation of

    EAAA.

  • Inhibit the expression of IL-17A and VEGF with siRNA attenuates experimental AAA progression and related inflammatory response.

  • IL-17A may influence the expression of VEGF via the JAK2/STAT3 signaling pathway.

Abstract

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, and Western 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 by WP1066. 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-17A and VEGF in vivo study; treatment with VEGF siRNA decreased the expression of VEGF, while IL-17A expression remained high. In an in vitro study, rhIL-17A treatment increased JAK2/STAT3 and VEGF expression in macrophages 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.

Keywords

Abdominal aortic aneurysm
JAK2/STAT3
WP1066
IL-17A
VEGF
Inflammation

Cited by (0)

1

Jie Xiao and Zhanjie Wei contributed equally to this work