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Disulfiram protects against abdominal aortic aneurysm by ameliorating vascular smooth muscle cells pyroptosis

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Abstract

Purpose

Recent studies demonstrated that pyroptosis is involved in abdominal aortic aneurysm (AAA) progression, suggesting a potential target for AAA treatment. This study aimed to identify if disulfiram could inhibit angiotensin II (Ang II)-induced vascular smooth muscle cells (VSMCs) damage, thereby exerting protective effects on AAA.

Methods

The AAA mouse model was established by continuous subcutaneous Ang II infusion for 28 days. Then aortic tissue of the mice was isolated and subjected to RNA sequencing, qRT-PCR, Western blotting, and immunofluorescence staining. To explore the therapeutic effect of disulfiram, mice were orally administered disulfiram (50 mg/kg/day) or vehicle for 28 days accompanied with Ang II infusion. Pathological changes in aortic tissues were measured using microultrasound imaging analysis and histopathological analysis. In addition, inflammatory response, pyroptosis, and oxidative stress damage were examined in mouse aortic vascular smooth muscle (MOVAS) cells stimulated with Ang II in vitro.

Results

The RNA sequencing and bioinformatic analysis results suggested that pyroptosis- and inflammation-related genes were significantly upregulated in AAA, consistent with the results of qRT-PCR and Western blotting. Most importantly, the therapeutic effect of disulfiram on AAA was identified in our study. First, disulfiram administration significantly attenuated Ang II-induced inflammation, pyroptosis, and oxidative stress in VSMCs, which is associated with the inhibition of the NF-κB-NLRP3 pathway. Second, in-vivo studies revealed that disulfiram treatment reduced AAA formation and significantly ameliorated collagen deposition and elastin degradation in the aortic wall.

Conclusion

Our findings suggest that disulfiram has a novel protective effect against AAA by inhibiting Ang II-induced VSMCs pyroptosis.

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Data availability

The data in the current study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (82070477, 81930007), Science and Technology Commission of Shanghai Municipality (19ZR1430400, 201409005200), Shanghai Hospital Development Center (SHDC12019X12), Shanghai “Rising Stars of Medical Talent” Youth Development Program “Outstanding Youth Medical Talents” (SHWSRS(2021)_099) and Shanghai Municipal Key Clinical Specialty (shslczdzk06204).

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Author notes

  1. Fei Liao, Ling Wang and Zhinan Wu contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Fei Liao, Zhinan Wu, Guqing Luo, Yuxuan Qian, Xinjie He, Song Ding & Jun Pu

  2. Department of Blood Transfusion, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Ling Wang

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  1. Fei Liao
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Contributions

S.D. conceived and supervised the study. F.L. and L.W. wrote the original draft of the manuscript. S.D. and J.P. revised the manuscript. F.L., L.W., Z.N.W., G.Q.L., Y.X.Q., and X.J.H. performed the experiments and analyzed the data.

Corresponding authors

Correspondence to Song Ding or Jun Pu.

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The authors of this manuscript declare no conflicts of interest.

Ethics approval

Experimental protocols were approved by the Animal Ethics Committee of Shanghai Jiao Tong University.

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Liao, F., Wang, L., Wu, Z. et al. Disulfiram protects against abdominal aortic aneurysm by ameliorating vascular smooth muscle cells pyroptosis. Cardiovasc Drugs Ther 37, 1–14 (2023). https://doi.org/10.1007/s10557-022-07352-w

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