Pharmacological Inhibition of Gasdermin D Suppresses Angiotensin II-Induced Experimental Abdominal Aortic Aneurysms

Jia Guo; Jinyun Shi; Min Qin; Yan Wang; Zhidong Li; Takahiro Shoji; Toru Ikezoe; Yingbin Ge; Baohui Xu

doi:10.3390/biom13060899

Pharmacological Inhibition of Gasdermin D Suppresses Angiotensin II-Induced Experimental Abdominal Aortic Aneurysms

Biomolecules. 2023 May 28;13(6):899. doi: 10.3390/biom13060899.

Authors

Jia Guo^{1

2}, Jinyun Shi¹, Min Qin¹, Yan Wang³, Zhidong Li⁴, Takahiro Shoji², Toru Ikezoe², Yingbin Ge⁵, Baohui Xu²

Affiliations

¹ Center for Hypertension Care, Shanxi Medical University First Hospital, Taiyuan 030001, China.
² Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China.
⁴ Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China.
⁵ Department of Physiology, Nanjing Medical University, Nanjing 211166, China.

Abstract

Background: Gasdermin D, a molecule downstream of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing inflammasome, forms the membrane pore for the secretion of interleukin (IL)-1β and IL-18, and also mediates pyroptosis. This study was to explore the influence of treatment with disulfiram, a small molecule inhibitor to gasdermin D, on the formation and progression of experimental abdominal aortic aneurysms (AAA).

Methods: AAAs were induced in 10-week-old male apolipoprotein E deficient mice by subcutaneous infusion of angiotensin II (1000 ng/min/kg body weight) for 28 days via osmotic minipumps. Three days prior to angiotensin II infusion, disulfiram (50 mg/kg) or an equal volume of saline as the vehicle control was administered daily via oral gavage. The influence on experimental AAAs was analyzed by serial measurements of aortic diameters via ultrasonography, grading AAA severity and histopathology at sacrifice. Serum IL-1β and IL-18 levels, systolic blood pressure, total cholesterol, and triglyceride were also measured. Additional experiments assayed the influences on the cell viability and IL-1β secretion of in vitro activated macrophages.

Results: Disulfiram significantly reduced the enlargement, incidence, and severity of angiotensin II-induced experimental AAAs with attenuation of medial elastin breaks, mural macrophage accumulation, and systolic blood pressure. The AAA suppression was also associated with reduced systemic levels of IL-1β but not IL-18. However, disulfiram treatment had no impact on body weight gain and lipid levels in aneurysmal mice. Additionally, disulfiram treatment also markedly reduced the secretion of IL-1β from activated macrophages with a limited effect on cell viability in vitro.

Conclusions: Gasdermin D inhibition by disulfiram attenuated angiotensin II-induced experimental AAAs with reduced systemic IL-1β levels and in vitro activated macrophage IL-1β secretion. Our study suggests that pharmacological gasdermin D inhibition may have translational potential for limiting clinical AAA progression.

Keywords: abdominal aortic aneurysms; disulfiram; gasdermin D; interleukin-1β; macrophages.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin II* / administration & dosage
Angiotensin II* / adverse effects
Angiotensin II* / therapeutic use
Animals
Aortic Aneurysm, Abdominal* / chemically induced
Aortic Aneurysm, Abdominal* / drug therapy
Aortic Aneurysm, Abdominal* / pathology
Body Weight
Disease Models, Animal
Disulfiram / pharmacology
Gasdermins / antagonists & inhibitors
Male
Mice
Mice, Inbred C57BL

Substances

Angiotensin II
Disulfiram
Gasdermins

Grants and funding

This work was supported by the National Natural Science Foundation of China (grant numbers: 81600256 and 82001248), Abroad Return Scholar Fund of Shanxi Province (grant number 2021-159), and Central Funds Guiding the Local Science and Technology Development (grant number Jincaijiao-2020165-Z135050009017).