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Dihydroartemisinin alleviates AngII-induced vascular smooth muscle cell proliferation and inflammatory response by blocking the FTO/NR4A3 axis

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Abstract

Objective

Inflammation and proliferation of vascular smooth muscle cells (VSMCs), induced by angiotensin II (AngII) and other growth factors, play important roles in the pathogenesis of hypertension, restenosis, and atherosclerosis. Dihydroartemisinin (DHA) exhibits broad protective effects. However, the effects of DHA on AngII-induced inflammation and proliferation of VSMCs remain unknown.

Materials and methods

AngII was used to construct VSMCs and vascular inflammation model in vitro and in vivo. The protective roles of DHA in inflammatory response and proliferation were evaluated through CCK-8, BrdU assay and immunofluorescence staining. The level of mRNA N6-methyladenosine was measured by m6A-RNA immunoprecipitation (MeRIP) assay. Western blot and quantitative real-time PCR were used to investigate the relationship between FTO and its potential downstream signaling molecules.

Results

In the present study, we found that DHA significantly suppressed AngII-induced proliferation of VSMCs and the expression of IL-6 and Ccl2 in a dose-dependent manner. Additionally, we confirmed that fat mass and obesity-associated (FTO) plays a critical role in AngII-induced VSMC proliferation and inflammation. FTO knockdown increased the methylation level of NR4A3 mRNA, whereas FTO, but not mutated FTO overexpression, reduced the methylation level of NR4A3 mRNA. These results suggest that DHA plays a protective role in AngII-induced VSMC proliferation and the associated inflammation by inhibiting the FTO/NR4A3 axis.

Conclusion

Our findings provide new insight into the mechanisms of DHA and its critical role in the pathogenesis of hypertension-related vascular complications.

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Acknowledgements

This study was partially supported by The Natural Science Foundation of Hebei Province (No. H2019206191 and H2021206161); This study was also supported by The government-funded clinical medicine outstanding talent training project (303-16-20-11) and High-level Talent Funding Project in Hebei Province (A202101059).

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Author notes

  1. Yan-Bing Huo and Xiang Gao contributed equally to this study.

Authors and Affiliations

  1. Department of Vascular Surgery, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, Hebei Province, People’s Republic of China

    Yan-Bing Huo, Xiang Gao & Wei Bi

  2. Department of Vascular Surgery, The Handan First Hospital, Handan, 056002, Hebei Province, People’s Republic of China

    Yan-Bing Huo & Qiang Nie

  3. Department of Hematology, The Handan First Hospital, Handan, 056002, Hebei Province, People’s Republic of China

    Qi Peng

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  1. Yan-Bing Huo
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Correspondence to Wei Bi.

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Huo, YB., Gao, X., Peng, Q. et al. Dihydroartemisinin alleviates AngII-induced vascular smooth muscle cell proliferation and inflammatory response by blocking the FTO/NR4A3 axis. Inflamm. Res. 71, 243–253 (2022). https://doi.org/10.1007/s00011-021-01533-3

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