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Angiotensin II‐Induced TLR4 Mediated Abdominal Aortic Aneurysm formation in ApoE‐/‐ mice is Dependent on STAT3

Abdominal Aortic Aneurysm (AAA) is a major cause of mortality and morbidity in older men. Angiotensin II (ANGII) treatment of ApoE‐/‐mice is a model for the study of the pathogenesis and treatment of AAA. Macrophage infiltration has been shown to play a role in the AAA formation. Here we demonstrate that ANGII mediates an increase in the phosphorylation of STAT3 in the suprarenal aorta from ApoE‐/‐ mice.The pSTAT3 inhibitor S3I‐201 decreased the incidence of AAA from 80% to 40% in these mice. A time course of the development of AAAs demonstrated that 7‐10 days after initiation of ANG II infusion, macrophage infiltration increased 3 fold compared to control and the number of macrophages with the M1 proinflammatory phenotype determined by FACS analysis of CD11c+ cells had increased 3 fold, with no change in the M2 CD206+ “healing” macrophages. Interestingly only 2 of 16 mice had developed AAAs at this time point. At day 28 of ANG II infusion 80% of 19 mice had developed AAAs, 67% of which demonstrated multiple clots and complex aneurysms. In these mice macrophages had increased 6 fold over control in extracts of the suprarenal aorta and the number of M1 macrophages had increased 6 fold by FACS and qPCR, while the number of M2 macrophages had decreased by 50% (N=6,n p<0.008). Treatment of mice with S3I‐201 reversed the ratio of M1 to M2 macrophages by 50%. In ApoE‐/‐ TLR4‐/‐ or in ApoE‐/‐ mice treated with ANGII and/or the small molecule TLR4 inhibitor Eritoran, levels of AAA formation, M1 macrophages and pSTAT3 levels decreased by 50%. These data support a role of pSTAT3 in TLR4 dependent AAA formation and a possible therapeutic role for TLR4 inhibition in AAA.