Abstract 18255: Inhibition of Toll-Like Receptor 4 Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation: Role of STAT3

Abdominal aortic aneurysm (AAA) is a potentially life-threatening degenerative vascular disease that affects 6-9% of men over 65. Toll-like receptors (TLRs) mediate the innate immune response resulting in the recruitment of inflammatory cells to the site of a range of pathogen-associated molecular patterns; they have also been implicated in many other inflammatory diseases such as cancer and atherosclerosis. It has been suggested by others that TLR4 might play a role in AAA formation. Objective: The purpose of this study was to determine whether TLR4 and its related Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway contributed to the development of angiotensin II (AngII)-induced AAA formation. Methods and Results: AngII (750 ng/kg/min) was infused into either ApoE-/- or ApoE-/-TLR4-/- male mice at 4 month old for 28 days using osmotic minipumps. The expression of TLR4 protein was significantly increased in aneurismal tissues compared to control aorta. TLR4 deficiency profoundly reduced AAA, with incidence of AAA formation of 82% versus 39%, with external aortic diameters of 1.88±0.13 mm versus 1.28±0.20 mm (n=18) respectively. STAT3 activation as measured by levels of pSTAT3 was increased in AngII treated ApoE-/- mice compared to vehicle treated, and was markedly reduced in AngII treated ApoE-/-TLR4-/- mice. Furthermore, the TLR4 antagonist, Eritoran attenuated AAA formation, with incidence of AAA formation of 80% versus 50%, with external aortic diameters of 1.92±0.15 mm versus 1.35±0.18 mm (n=9) respectively. Eritoran treatment also decreased pSTAT3 in AngII-treated ApoE-/- mice. The JAK/STAT3 can be driven by both AngII and TLR4 signaling. In order to determine the role of STAT3 in AAA formation, S3I-201, an inhibitor of STAT3 was administrated. AngII-induced AAA formation in ApoE-/- was significantly prevented by S3I-201 treatment (5mg/kg, IP, QOD) with incidence of AAA formation of 85% versus 40%, with external aortic diameters of 1.90±0.16 mm versus 1.15±0.10 mm (n=15) respectively. Conclusions: These studies demonstrated that inhibition of TLR4 reduces AngII-induced AAA via a STAT3 dependent mechanism suggesting that selective targeting of STAT3 may have substantial therapeutic potential.