Impairment Of Autophagic Function Promotes Development Of Abdominal Aortic Aneurysm And Metabolic Syndrome

Metabolic syndrome (MS) is characterized by up-regulation of circulating insulin level, hepatic lipid accumulation and steatosis, insulin resistance and oral glucose tolerance, leading to high morbidity and mortality. Abdominal aortic aneurysm (AAA), which is characterized by the expansion of abdominal aorta, loss of aortic cells, destruction of medial elastic fibers and high risk of aortic rupture, is one of common complications of metabolic syndrome. Chronic inflammation contributes both of MS and AAA. Abundant studies proved autophagy restricts excessive inflammation, indicating the critical role of autophagy in mediating MS and AAA. To investigate the protective effects of autophagy, human AAA sample, LPS or Ang II-treated T/G HA-VSMC, Ang II-induced AAA in mice, and high fat diet fed mice were used. In human AAA sample, LPS-treated T/G HA-VSMC and livers of high fat diet fed mice, levels of phosphoralated inflammatory nuclear factor NF-kB p65and IL-6, IL-8(CXCL-8) expression were up-regulated, which are accompanied by increasing ROS and cellular senescence-related βgal-positive cells. In human AAA sample and LPS-treated T/G HA-VSMC, we have found senescence-related p53-p21CIPl-RB signal and apoptosis-related cleaved caspase3expression were over-expressed. Moreover, abundant hepatic fibrosis was found in high fat diet fed mice. Up-regulation of autophagy-related PI3K3C and beclinl expression, the transition from LC3I to LC3II were observed in human AAA sample, LPS-treated T/G HA-VSMC and livers of high fat diet fed mice. However, autophagic substrate insoluble p62content also were up-regulated. Moreover, more lipid accumulation in livers of high fat diet fed mice was found, indicating activated autophagic signals and blocked autophagic flux. Furthermore, in human AAA sample, LPS-treated T/G HA-VSMC and livers of high fat diet fed mice, we found trribles homolog3(TRB3) interfered p62, and disturbing TRB3-p62conjunction significantly activated autophagic flux, which is accompanied by decreased levels of IL-6, IL-8(CXCL-8) expression, ROS and cellular senescence. Moreover, disturbing TRB3-p62conjunction attenuated cleaved caspase3expression in LPS or Ang II-treated T/G HA-VSMC, and improved hepatic hypertrophy and pathology, circulating insulin and IGF-1and glucose tolerance in high fat diet fed mice. In conclusion, we proved the critical role of autophagy in mediating MS and AAA, the results of this study will not only contribute to understanding the pathogenesis of MS and AAA, but also provide the research clues for the development of new anti-MS or AAA drugs.