Background: Abdominal aortic aneurysm (AAA), characterized by a continued expansion of the aorta, leads to rupture if not surgically repaired. Mice aid the study of disease progression and its underlying mechanisms since sequential studies of aneurysm development are not feasible in humans. The present study used unbiased proteomics and systems biology to understand the molecular relationship between the mouse models of AAA and the human disease. Methods and results: Aortic tissues of developing and established aneurysms produced by either angiotensin II (AngII) infusion in Apoe−/− and Ldlr−/− mice or intraluminal elastase incubation in wildtype C57BL/6J mice were examined. Aortas were dissected free and separated into eight anatomical segments for proteomics in comparison to their appropriate controls. High-dimensional proteome cluster analyses identified site-specific protein signatures in the suprarenal segment for AngII-infused mice (159 for Apoe−/− and 158 for Ldlr−/−) and the infrarenal segment for elastase-incubated mice (173). Network analysis revealed a predominance of inflammatory and coagulation factors in developing aneurysms, and a predominance of fibrosis-related pathways in established aneurysms for both models. To further substantiate our discovery platform, proteomics was performed on human infrarenal aortic aneurysm tissues as well as aortic tissue collected from age-matched controls. Protein processing and inflammatory pathways, particularly neutrophil-associated inflammation, dominated the proteome of the human aneurysm abdominal tissue. Aneurysmal tissue from both mouse and human had inflammation, coagulation, and protein processing signatures, but differed in the prevalence of neutrophil-associated pathways, and erythrocyte and oxidative stress-dominated networks in the human aneurysms. Conclusions: Identifying changes unique to each mouse model will help to contextualize model-specific findings. Focusing on shared proteins between mouse experimental models or between mouse and human tissues may help to better understand the mechanisms for AAA and establish molecular bases for novel therapies.
|Journal||Frontiers in Cardiovascular Medicine|
|State||Published - Aug 3 2022|
Bibliographical noteFunding Information:
Author HH is an employee of Kowa and was visiting scientist at Brigham and Women's Hospital when the study was conducted. Author MA has received research grants from Pfizer and Sanofi. Author PL is an unpaid consultant to or involved in clinical trials for Amgen, AstraZeneca, Esperion Therapeutics, Ionis Pharmaceuticals, Kowa, Novartis, Pfizer, Sanofi-Regeneron, and XBiotech, is a member of scientific advisory board for Amgen, Corvidia Therapeutics, DalCor Pharmaceuticals, IFM Therapeutics, Kowa, Olatec Therapeutics, Medimmune, Novartis, and XBiotech, and serves on the Board of XBiotech. The laboratory of PL has received research funding in the last 2 years from Novartis. Author PL has a financial interest in Xbiotech. His interests were reviewed and are managed by Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This study was primarily supported by a research grant from Kowa Company, Ltd., Nagoya, Japan (to MA), which was not involved in the study design, experiments, data acquisition, and preparation of the manuscript, and in part by the grants from the National Heart, Lung, and Blood Institute (R01HL126901 and R01HL149302 to MA; R01HL136431, R01HL141917, and R01HL147095 to EA; R01HL080472 and R01HL134892 to PL; R01HL133723 and R35HL155649 to AD; R99HL116786 and R01HL147171 to AO; and R01HL158801 to SC).
Copyright © 2022 Morgan, Lee, Halu, Nicolau, Higashi, Ha, Wen, Daugherty, Libby, Cameron, Mix, Aikawa, Owens, Singh and Aikawa.
- angiotensin II
- mouse model
- network analysis
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine