Abstract 14738: Inflammasome Activation by Mitochondrial Oxidative Stress in Macrophages Leads to the Development of Angiotensin II-induced Aortic Aneurysm
Introduction: 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 formation remains unclear. The NLRP3 inflammasome is a multiprotein complex consisting of NLRP3, ASC, and caspase-1, and regulates caspase-1-dependent maturation of interleukin-1β (IL-1β). We previously showed that the NLRP3 inflammasome mediates the sterile cardiovascular inflammatory responses in vascular injury and myocardial ischemia-reperfusion injury.
Hypothesis: We hypothesized that the NLRP3 inflammasome is a key mediator of initial inflammation in AAA formation.
Methods: ASC 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 (AII) for 28 days in Apoe-/- mice, NLRP3, ASC, and caspase-1 deficiency in Apoe-/- mice was shown to significantly decrease the incidence, maximal diameter, and severity of AAA along with adventitial fibrosis and inflammatory responses, such as inflammatory cell infiltration and cytokine expression in the vessel wall. Blood pressures and lipid profiles were not influenced by the NLRP3 inflammasome deficiency. NLRP3, ASC, and caspase-1 deficiency in Apoe-/- mice also reduced elastic lamina degradation and metalloproteinase activation in the early phase of AAA formation. Further, AII stimulated generation of mitochondria-derived reactive oxygen species (mtROS) in the adventitial macrophages, and this mtROS generation was inhibited by NLRP3, ASC, and caspase-1 deficiency. In vitro experiments revealed that AII stimulated the NLRP3 inflammasome activation and subsequent IL-1β release in macrophages, and this activation was mediated through an AT1R/mtROS-dependent pathway.
Conclusions: Our results demonstrate the importance of the NLRP3 inflammasome in the initial inflammatory responses in AAA formation, indicating its potential as a novel therapeutic target for preventing AAA progression.
Author Disclosures: M. Takahashi: None. F. Usui: None. A. Kawashima: None. T. Karasawa: None. H. Kimura: None.
- © 2014 by American Heart Association, Inc.