Identifying novel mechanisms of abdominal aortic aneurysm via unbiased proteomics and systems biology

Stephanie Morgan; Lang Ho Lee; Arda Halu; Jessica S. Nicolau; Hideyuki Higashi; Anna H. Ha; Jennifer R. Wen; Alan Daugherty; Peter Libby; Scott J. Cameron; Doran Mix; Elena Aikawa; A. Phillip Owens; Sasha A. Singh; Masanori Aikawa

doi:10.3389/fcvm.2022.889994

Identifying novel mechanisms of abdominal aortic aneurysm via unbiased proteomics and systems biology

Stephanie Morgan, Lang Ho Lee, Arda Halu, Jessica S. Nicolau, Hideyuki Higashi, Anna H. Ha, Jennifer R. Wen, Alan Daugherty, Peter Libby, Scott J. Cameron, Doran Mix, Elena Aikawa, A. Phillip Owens, Sasha A. Singh, Masanori Aikawa

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

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.

Original language	English
Article number	889994
Journal	Frontiers in Cardiovascular Medicine
Volume	9
DOIs	https://doi.org/10.3389/fcvm.2022.889994
State	Published - Aug 3 2022

Bibliographical note

Funding 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.

Funding Information:
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).

Publisher Copyright:
Copyright © 2022 Morgan, Lee, Halu, Nicolau, Higashi, Ha, Wen, Daugherty, Libby, Cameron, Mix, Aikawa, Owens, Singh and Aikawa.

Keywords

angiotensin II
elastase
inflammation
mouse model
network analysis
thrombosis

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3389/fcvm.2022.889994

Cite this

Morgan, S., Lee, L. H., Halu, A., Nicolau, J. S., Higashi, H., Ha, A. H., Wen, J. R., Daugherty, A., Libby, P., Cameron, S. J., Mix, D., Aikawa, E., Owens, A. P., Singh, S. A., & Aikawa, M. (2022). Identifying novel mechanisms of abdominal aortic aneurysm via unbiased proteomics and systems biology. Frontiers in Cardiovascular Medicine, 9, [889994]. https://doi.org/10.3389/fcvm.2022.889994

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title = "Identifying novel mechanisms of abdominal aortic aneurysm via unbiased proteomics and systems biology",

abstract = "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.",

keywords = "angiotensin II, elastase, inflammation, mouse model, network analysis, thrombosis",

author = "Stephanie Morgan and Lee, {Lang Ho} and Arda Halu and Nicolau, {Jessica S.} and Hideyuki Higashi and Ha, {Anna H.} and Wen, {Jennifer R.} and Alan Daugherty and Peter Libby and Cameron, {Scott J.} and Doran Mix and Elena Aikawa and Owens, {A. Phillip} and Singh, {Sasha A.} and Masanori Aikawa",

note = "Funding 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. Funding Information: 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). Publisher Copyright: Copyright {\textcopyright} 2022 Morgan, Lee, Halu, Nicolau, Higashi, Ha, Wen, Daugherty, Libby, Cameron, Mix, Aikawa, Owens, Singh and Aikawa.",

year = "2022",

month = aug,

day = "3",

doi = "10.3389/fcvm.2022.889994",

language = "English",

volume = "9",

journal = "Frontiers in Cardiovascular Medicine",

issn = "2297-055X",

publisher = "Frontiers Media S.A.",

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TY - JOUR

T1 - Identifying novel mechanisms of abdominal aortic aneurysm via unbiased proteomics and systems biology

AU - Morgan, Stephanie

AU - Lee, Lang Ho

AU - Halu, Arda

AU - Nicolau, Jessica S.

AU - Higashi, Hideyuki

AU - Ha, Anna H.

AU - Wen, Jennifer R.

AU - Daugherty, Alan

AU - Libby, Peter

AU - Cameron, Scott J.

AU - Mix, Doran

AU - Aikawa, Elena

AU - Owens, A. Phillip

AU - Singh, Sasha A.

AU - Aikawa, Masanori

N1 - Funding 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. Funding Information: 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). Publisher Copyright: Copyright © 2022 Morgan, Lee, Halu, Nicolau, Higashi, Ha, Wen, Daugherty, Libby, Cameron, Mix, Aikawa, Owens, Singh and Aikawa.

PY - 2022/8/3

Y1 - 2022/8/3

N2 - 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.

AB - 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.

KW - angiotensin II

KW - elastase

KW - inflammation

KW - mouse model

KW - network analysis

KW - thrombosis

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U2 - 10.3389/fcvm.2022.889994

DO - 10.3389/fcvm.2022.889994

M3 - Article

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SN - 2297-055X

VL - 9

JO - Frontiers in Cardiovascular Medicine

JF - Frontiers in Cardiovascular Medicine

M1 - 889994

ER -

Identifying novel mechanisms of abdominal aortic aneurysm via unbiased proteomics and systems biology

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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