Si-Miao-Yong-An Decoction alleviates thromboangiitis obliterans by regulating miR-548j-5p/IL-17A signaling pathway

Abstract

Thromboangiitis obliterans (TAO) is a rare, chronic, progressive, and segmental inflammatory disease characterized by a high rate of amputation, significantly compromising the quality of life of patients. Si-Miao-Yong-An decoction (SMYA), a traditional prescription, exhibits anti-inflammatory, anti-thrombotic, and various other pharmacological properties. Clinically, it was fully proved to be effective for TAO therapy, but the specific therapeutic effect of SMYA on TAO has been unknown. Thus, deep unveiling the mechanism of SMYA in TAO for identifying clinical therapeutic targets is extremely important. In this study, we observed elevated levels of IL-17A in the peripheral blood mononuclear cells (PBMCs) of TAO patients, whereas the expression of miR-548j-5p was significantly decreased. A negative correlation between the levels of miR-548j-5p and IL-17A was also demonstrated. In vitro experiments showed that overexpression of miR-548j-5p led to a decrease in IL-17A levels, whereas downregulation of miR-548j-5p showed the opposite effect. Using a dual luciferase assay, we confirmed that miR-548j-5p directly targets IL-17A. Furthermore, serum containing SMYA effectively decreased IL-17A levels by increasing the expression of miR-548j-5p. More importantly, the results of in vivo tests indicated that SMYA mitigated the development of TAO by inhibiting IL-17A through the upregulation of miR-548j-5p in vascular tissues. In conclusion, SMYA significantly enhances the expression of miR-548j-5p, thereby reducing the levels of the target gene IL-17A and alleviating TAO. Our research not only identifies novel targets and pathways for the clinical diagnosis and treatment of TAO but also advances the innovation in traditional Chinese medicine through the elucidation of the SMYA/miR-548j-5p/IL-17A regulatory axis in the pathogenesis of TAO.

Keywords

Thromboangiitis obliterans / IL-17A / Inflammation / miR-548j-5p / Si-Miao-Yong-An Decoction

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Funding

Natural Science Foundation of China(82274575)

Co-construction Project of State Administration of TCM(GZY-KJS-SD-2023-034)

Co-construction Project of State Administration of TCM(GZY-KJS-SD-2023-046)

Major Basic Research Project of Natural Science Foundation of Shandong Province(ZR2023ZD56)

Joint Fund of Natural Science Foundation of Shandong(ZR2022LZY011)

Central Government Guides Local Science and Technology Development Fund Projects of Shandong Province(YDZX20203700001407)

Taishan Scholars(Tsqn201812125)

National Youth Qihuang Scholar Training Program, Shandong Province Traditional Chinese Medicine High Level Talent Cultivation Project and Key research and development project of Shandong Province(2020CXGC010505)