The age-associated increase of aseptic in ammation and necroptosis are closely related to the emergence of various age-associated diseases. MethodsIn this study, the role of HMGB1/TLR4-induced necroptosis in abdominal aortic aneurysm (AAA) formation was investigated. Firstly, the levels of sterile in ammatory mediators (HMGB1, TLR4) and necroptosis markers in the abdominal aorta of adult and old C57BL/6J mice were tested. We observed that sterile in ammatory 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. ResultsWe 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 signi cantly, and the progression of AAA was also alleviated in APOE −/ − mice. ConclusionsOur results indicate that HMGB1/TLR4-mediated necroptosis enhances AAA development in Ang IIinduced AAA model of APOE −/− mice and the possible therapeutic roles for TLR4 inhibition in AAA.

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.

Objective Sirtuin 6 (SIRT6) is a nuclear deacetylase regulating lifespan. Previous articles had reported a causal link between cell senescence and aneurysm. In this study, we carried out clinical sample study, in vivo study and in vitro study to determine the effect of SIRT6 and SIRT6 mediated vascular smooth muscle senescence on the development of AAA (abdominal aortic aneurysm) Methods Aortic specimens were collected from AAA patients and organ donors. AAA was inducted in ApoE−/− mice by Angiotensin II infusion. In vivo overexpression of SIRT6 was achieved by transgenic method. Human aortic smooth muscle cells (HASMC) were used in the in vitro study. In vitro knockdown and overexpression of SIRT6 was achieved by lentivirus transfection. Results AAA specimen showed an increased P16, P21 level and a decreased SIRT6 level compared with control aorta. Time cause study of Ang II infusion model showed similar P16, P21 and SIRT6 change at the early phase of AAA induction. The in vivo overexpression of SIRT6 significantly prevented AAA formation in Ang II infusion model. The expression of senescent biomarker, P16 and P21 were significantly reduced after SIRT6 overexpression. SIRT6 overexpression also attenuated chronic inflammation and neo-angiogenesis in Ang II infusion model. Ang II could induce premature senescence in HASMC. The overexpression of SIRT6 could attenuated premature senescence, inflammatory response and neo-angiogenesis in HASMC under Ang II stimulation. Conclusion SIRT6 overexpression could limit AAA formation via attenuate vascular smooth muscle senescence, chronic inflammation and neovascularity.