A bdominal aortic aneurysm (AAA) is an age-related disease that occurs in ≤9% of adults aged of ≥65 years and is responsible for a significant number of deaths in Western countries.1 Although aggressive management of hypertension and hyperlipidemia is recommended in patients with AAA, these strategies have only little effect on the progression of AAA. Surgery is the only treatment for patients with AAA, but this is costly and associated with high morbidity and mortality.2 Endovascular repair is associated with lower postoperative mortality rates as compared to open surgical repair; however, there are no significant differences in total mortality or AAA-related mortality in the long term, with a higher incidence of reintervention in endovascular repair.3 When surgical treatment is not possible, AAAs typically progress to rupture with high mortality primarily because no effective nonsurgical treatment is currently available. Thus, a better understanding of the underlying mechanisms involved in AAA formation may help in identifying new therapeutic targets that could suppress AAA progression and reduce the risk of rupture.© 2014 American Heart Association, Inc. Objective-Abdominal aortic aneurysm (AAA) is considered a chronic inflammatory disease; however, the molecular basis underlying the sterile inflammatory response involved in the process of AAA remains unclear. We previously showed that the inflammasome, which regulates the caspase-1-dependent interleukin-1β production, mediates the sterile cardiovascular inflammatory responses. Therefore, we hypothesized that the inflammasome is a key mediator of initial inflammation in AAA formation. Approach and Results-Apoptosis-associated speck-like protein containing a caspase recruitment domain is highly expressed in adventitial macrophages in human and murine AAA tissues. Using an established mouse model of AAA induced by continuous infusion of angiotensin II in Apoe -/-mice, NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase-1 deficiency in Apoe -/-mice were shown to decrease the incidence, maximal diameter, and severity of AAA along with adventitial fibrosis and inflammatory responses significantly, such as inflammatory cell infiltration and cytokine expression in the vessel wall. NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase-1 deficiency in Apoe -/-mice also reduced elastic lamina degradation and metalloproteinase activation in the early phase of AAA formation. Furthermore, angiotensin II stimulated generation of mitochondria-derived reactive oxygen species in the adventitial macrophages, and this mitochondria-derived reactive oxygen species generation was inhibited by NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase-1 deficiency. In vitro experiments revealed that angiotensin II stimulated the NLRP3 inflammasome activation and subsequent interleukin-1β release in macrophages,...

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