Abstract 317: Inflammasome Inhibitor MCC950 Prevents the Development of Sporadic Thoracic and Abdominal Aortic Aneurysms and Dissections in Mice

Abstract

Background: Aortic aneurysms and dissections (AAD) are common interrelated cardiovascular diseases that cause more than 10,000 deaths in the United States each year and are a leading cause of death in people 55 years of age or older. Currently, surgery is the only effective treatment; thus, there is a critical need to develop pharmacological agents that can prevent the initiation or progression of AAD. Increasing evidence suggests that the NLRP3 inflammasome plays a critical role in aortic destruction. In this study, we aimed to test the therapeutic potential of MCC950, a potent and specific NLRP3 inhibitor, for preventing AAD. Methods/Results: In a sporadic AAD model induced by a high-fat diet and angiotensin II infusion,, aortic challenge induced significant aortic enlargement and the development of a range of AAD manifestations, including aneurysm without dissection, dissection, and rupture. Importantly, MCC950 treatment significantly inhibited aortic enlargement and the development of AAD, particularly in the ascending and suprarenal aorta. The overall incidence of AAD decreased from 86% in the challenged control group to 40% in the challenged MCC950 treatment group ( P <0.001). The incidence of ascending AAD decreased from 56% in the challenged control group to 18% in the challenged MCC950 treatment group ( P =0.0001), and the incidence of suprarenal AAD decreased from 60% in the challenged control group to 20% in the challenged MCC950 treatment group ( P <0.001). The reduction in AAD incidence was similar in male and female mice. Furthermore, aortas from the MCC950 group showed reductions in inflammasome activation, macrophage infiltration, MMP-9 activity, and elastic fiber destruction. Likewise, in the cultured macrophages, MCC950 treatment inhibited H 2 O 2 -induced activation of the NLRP3 inflammasome, IL-1β secretion, and MMP-9 activation. Conclusion: The NLRP3 inhibitor MCC950 is effective at preventing inflammasome activation, aortic destruction, inflammation, and the development of AAD in a mouse model of sporadic disease. Further studies are needed to determine whether MCC950 has similar effects in other AAD models.