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.

GSDMD Deficiency Protects Against Aortic Rupture