The annual incidence of abdominal aortic aneurysm (AAA) is approximately 0.4% to 0.67% in Western populations on average. Without timely surgical treatment, AAA can progress to life-threatening rupture with mortality rates as high as 80%, which ranks the 15th leading cause of death in the United States. AAA development is progressively increasing with renal dysfunction. Chronic kidney disease (CKD), an independent risk factor for AAA, is a progressive disease that affects >10% of the general population worldwide. In the United States, 2023, the Centers for Disease Control and Prevention reported that 14% of US adults are estimated to have CKD. Among 153 uremic toxins which are accumulated in plasma of CKD patients, Trimethylamine N-oxide (TMAO) has recently emerged as a gut microbiota-generated uremic toxin and the plasma TMAO levels are significantly elevated in patients with CKD and AAA. However, the role of TMAO in promoting endothelial cell activation, vascular inflammation and progression of AAA remains unclear. The non-canonical inflammasome activation has been described as a pathway that is dependent on caspase-4 (human) and caspase-11 (mice) in response cytosolic Lipopolysaccharide (LPS) stimulation. The activated caspase-4/11 will trigger the cleavage of Gasdermin D (GSDMD) and the formation of N-terminal GSDMD cell membrane pore. Then, the proinflammatory cytokines such as IL-1b will be released. However, the role of caspase-11 pathway in abdominal aortic aneurysm remains unknown. We hypothesize that TMAO promotes endothelial cell activation, vascular inflammation, and progression of AAA via caspase-11 pathway; the deficiency of caspase-11 will inhibit the development of AAA. In this project, we demonstrated the role of TMAO in promoting endothelial cell activation, vascular inflammation and accelerating the progression of abdominal aortic aneurysm. We performed histological study to demonstrate that the vascular structure was damaged including increased elastin breaks and non-uniform collagen deposition in TMAO promoted Angiotensin II (Ang II)-induced AAA in Apolipoprotein E (ApoE) KO background. In addition, we performed myograph for determine endothelial vascular dysfunction and found that the endothelial-dependent vessel relaxation to acetylcholine (ACh) was damaged by TMAO stimulation, but endothelial-independent vessel relaxation to Sodium nitroprusside (SNP) was not affected by Ang II+TMAO. For mechanism study, we found that the TMAO receptor eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, also known as PERK) pathway activation, increased cytosolic LPS, increased activation of caspase-11 and increased proinflammatory cytokine release in aorta of Ang II-TMAO-induced AAA. Finally, we found that caspase-11 was required for Ang II-TMAO-induced trained immunity (also known as innate immune memory) and the progression of Ang II-TMAO-induced AAA was significantly inhibited in caspase-11/ApoE double knockout (DKO) mice compared to ApoE KO mice. Caspase-11 can be identified as a potential therapeutic target for inhibiting trained immunity and progression of AAA. / Biomedical Sciences
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/10196 |
| Date | 03 1900 |
| Creators | Lu, Yifan |
| Contributors | Yang, Xiaofeng, Khan, Mohsin, Wang, Hong, 1956 September 19-, Snyder, Nathaniel, Sun, Jianxin |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 121 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/10158, Theses and Dissertations |
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