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Statin therapy protects against abdominal aortic aneurysms by inducing the accumulation of regulatory T cells in ApoE−/− mice

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Abstract

CD4+CD25+ regulatory T cells (Tregs) have been shown to protect against abdominal aortic aneurysm (AAA) progression. Statins have immunomodulatory properties, and their effect on AAA partly depends on immune-related mechanisms. In this study, we aimed to explore whether there is an association between statins and Tregs in AAA progression. Sixty ApoE−/− mice were randomly divided into four groups (n = 15 per group): A, saline group; B, control group; C, simvastatin group (intragastric administration of simvastatin); and D, PC61 group (simvastatin combined with an intraperitoneal injection of 100 μg CD25-depleting antibody PC61). After 2 weeks of simvastatin treatment, the mice received a continuous subcutaneous infusion of angiotensin II (Ang II; B, C, and D groups) or saline (A group) for 28 days. Simvastatin therapy for 6 weeks significantly decreased the incidence and severity of AAA and inhibited the apoptosis of smooth muscle cells and generation of reactive oxygen species, which was partly abolished after the injection of PC61 antibody. Importantly, simvastatin increased the number of Tregs and the levels of Treg-associated cytokines (TGF-β and IL-10) and decreased the level of IL-17 both in aortic tissues and serum. Interestingly, simvastatin attenuated Ang II-induced gut microbial dysbiosis, which might be associated with the accumulation of Tregs. In conclusion, simvastatin therapy prevented the development of AAA induced by Ang II in ApoE−/− mice, which might be partly due to the induction of Treg accumulation. In addition, simvastatin regulated gut microbial dysbiosis, which might also be associated with Treg generation.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request.

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Funding

This work was supported by the grants of the National Natural Science Foundation of China (No. 81970319) and the Taishan Scholars Program of Shandong Province (No. tsqn202103170).

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Authors and Affiliations

  1. The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China

    Linlin Meng, Yue Lu, Xinlu Wang, Wenhai Sui, Xiao Ge, Ming Zhong, Xiao Meng & Yun Zhang

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  1. Linlin Meng
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  3. Xinlu Wang
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Contributions

XM and YZ designed the study. LLM performed the experiments, analyzed the data, and wrote the manuscript. YL, XLW, and XG contributed to the performing of the experiments. WHS and MZ contributed in the revision of the manuscript. All the authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xiao Meng or Yun Zhang.

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Animal care and experimental procedures were approved by the Animal Ethics Committee of Shandong University and performed according to the Animal Management Rules of the Chinese Ministry of Health.

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The authors declare no competing interests.

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Key messages

• Simvastatin therapy protected against AAA development in ApoE-/- mice by inducing the accumulation of Tregs in aortic tissues, which decreased the SMC apoptosis of smooth muscle cells and ROS generation.

• The accumulation of Tregs in aortic tissues promoted local anti-inflammatory responses.

• The accumulation of Tregs in aortic tissues may be partly related to the improvement of gut microbiota induced by simvastatin therapy.

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Meng, L., Lu, Y., Wang, X. et al. Statin therapy protects against abdominal aortic aneurysms by inducing the accumulation of regulatory T cells in ApoE−/− mice. J Mol Med 100, 1057–1070 (2022). https://doi.org/10.1007/s00109-022-02213-3

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  • DOI: https://doi.org/10.1007/s00109-022-02213-3

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