ABSTRACT
Objective Aortic ruptures are fatal consequences of aortic aneurysms with macrophage accumulation being a hallmark at the site of ruptures. Pyroptosis is critical in macrophage-mediated inflammation. This study determined effects of pyroptosis on aortic dilation and rupture using GSDMD deficient mice.
Approach and Results In an initial study, male Gsdmd+/+ and Gsdmd-/- mice in C57BL/6J background (8 – 10 weeks old) were infected with adeno-associated viral vectors encoding mouse PCSK9D377Y gain-of-function mutation and fed a Western diet to induce hypercholesterolemia. After two weeks of AAV infection, angiotensin II (AngII, 1 µg/kg/min) was infused. During the 4 weeks of AngII infusion, 5 of 13 Gsdmd+/+ mice died of aortic rupture, whereas no aortic rupture occurred in Gsdmd-/- mice. In surviving mice, no differences in either ascending or abdominal aortic dilation were observed between Gsdmd+/+ and Gsdmd-/- mice. To determine whether protection of GSDMD deficiency against aortic rupture is specific to AngII infusion, we subsequently examined aortic pathologies in mice administered beta-aminopropionitrile (BAPN). BAPN (0.5% wt/vol) was administered in drinking water to male Gsdmd+/+ and Gsdmd-/- mice (4 weeks old) for 4 weeks. Six of 13 Gsdmd+/+ mice died of aortic rupture, whereas no aortic rupture occurred in Gsdmd-/- mice. In mice survived, no differences of diameters in the ascending, arch, or abdominal aortic regions were observed between Gsdmd+/+ and Gsdmd-/- mice.
Conclusions GSDMD deficiency protects against AngII or BAPN-induced aortic ruptures in mice.
Highlights
GSDMD deficiency protects against angiotensin II-induced aortic rupture in hypercholesterolemic mice.
GSDMD deficiency protects against beta-aminopropionitrile (BAPN)-induced aortic dissection and rupture in C57BL/6J mice.
Competing Interest Statement
The authors (CW, HSL, AD, and ZL) have filed a patent application (treatment for aortopathy targeting GSDMD) in June 2020.
Non-standard abbreviations
- AAV
- adeno-associated viral vectors
- AngII
- angiotensin II
- AAAs
- abdominal aortic aneurysms
- BAPN
- beta-aminopropionitrile
- GSDMD
- gasdermin D