HMGB1/TLR4 Signaling Pathway Enhances Abdominal Aortic Aneurysm Progression in Mice by Upregulating Necroptosis

Abstract

Abstract Objective and design: The age-associated increase of aseptic inflammation and necroptosis are closely related to the emergence of various age-associated diseases. Methods In this study, the role of HMGB1/TLR4-induced necroptosis in abdominal aortic aneurysm (AAA) formation was investigated. Firstly, the levels of sterile inflammatory mediators (HMGB1, TLR4) and necroptosis markers in the abdominal aorta of adult and old C57BL/6J mice were tested. We observed that sterile inflammatory mediators and necroptosis markers were greatly increased in old mice’s abdominal aorta. Then, using angiotensin II (Ang II)-induced AAA model of APOE−/− mice, the models were treated with RIP1 inhibitor Necrostatin-1 (Nec-1), TLR4 inhibitor TAK-242, respectively. Results We found that HMGB1, TLR4, and necroptosis markers were elevated with the development of AAA in APOE−/− mice. In addition, necroptosis inhibition by Nec-1 alleviated Ang II-induced AAA development, while the expressions of HMGB1/TLR4 declined. Notably, after blocking TLR4 by TAK-242, the expression of necroptosis markers decreased significantly, and the progression of AAA was also alleviated in APOE−/− mice. Conclusions Our results indicate that HMGB1/TLR4-mediated necroptosis enhances AAA development in Ang II-induced AAA model of APOE−/− mice and the possible therapeutic roles for TLR4 inhibition in AAA.