liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Targeting vascular remodeling in abdominal aortic aneurysm: To identify novel treatment strategies and drug candidates
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Abdominal aortic aneurysm (AAA) is a degenerative weakening of the aortic wall, mainly affecting elderly men with a prevalence of 4.4-7.7 %. AAA is characterized by medial and adventitial inflammatory cell infiltration associated with vascular remodeling of the extracellular matrix proteins such as collagen and elastin and with phenotypic modulation and loss of vascular smooth muscle cells (VSMCs). Although much research has been performed, the precise cellular and molecular pathways behind these processes are still poorly understood. The overall aim of this thesis was to target signaling pathways that affect vascular remodeling of AAA to potentially identify novel strategies and drug candidates for future treatment of aneurysmal diseases. In order to develop our understanding of the pathophysiology of AAA, we used the angiotensin (Ang) II-induced AAA animal model and human biopsies taken at end-stage of disease to recapitulate key aspects of disease formation.

Innate immune receptors such as toll-like receptors (TLRs) are known to regulate immunological processes leading to the formation and progression of vascular disease including AAA. In paper I, we aimed to investigate the role of TLR signaling under the control of the TRIF adaptor protein in the formation of AAA. Human, aneurysmal aortas displayed increased expression of TLR3 and TLR4 in surface of macrophages and T lymphocytes. AngII-induced aneurysm formation was attenuated in mice lacking the Trif gene  (ApoE-/-Triʃ-/-), and these knockout mice presented with a more intact medial layer together with a reduced inflammatory response by macrophages and T lymphocytes and reduced levels of pro-inflammatory cytokines, chemokines, and proteases. Our results suggest an involvement of TRIF in the pathophysiology of AAA.

Current management of AAA fully depends on imaging and surgical techniques, and drug-based therapies are still mostly ineffective. In paper II, we aimed to investigate the potential protective role of the tyrosine kinase inhibitor imatinib on the molecular mechanism involved in AAA formation. In AngII-infused ApoE-/-mice, 10 mg/kg imatinib per day affected several key features important in aneurysmal formation, including  preservation of the medial layer of the VSMCs, reduced infiltrations of CD3ε-positive T lymphocytes, and reduced gene expression of mast cell chymase, resulting in decreased aortic diameter and vessel wall thickness. These results highlight the importance of the tyrosine kinase inhibitor imatinib as a potential drug in the treatment of pathological vascular inflammation and remodeling in conditions such as AAA.

In paper III, we aimed to investigate the role of adiponectin in experimentally induced AAA formation in mice. In mice with elevated adiponectin levels, AAA development was inhibited, and this was associated with reduced inflammatory cell infiltration, reduced medial degeneration of VSMCs and of elastin in the aortic vessel wall together with an improved systemic cytokine profile and the attenuation of periaortic adipose tissue (PVAT) inflammation. These results support the protective effect of adiponectin in the remodeling occurring in the aortic wall and in the prevention of AAA.

In paper IV, we performed a descriptive study investigating the composition of PVAT adjacent to the aneurysmal aorta. We used immunohistochemistry to identify neutrophils, macrophages, mast cells, and T lymphocytes surrounding necrotic adipocytes in PVAT together with increased gene expression of IL-6 and cathepsin K and S. We also determined the concentrations of pro-inflammatory ceramides in PVAT and found an association to T lymphocytes. These results suggest that inflamed adipose tissue might be a source of proinflammatory cells and mediators that contribute to aortic wall degeneration.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. , 82 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1512
National Category
Medicinal Chemistry Medical Biotechnology Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-127502DOI: 10.3384/diss.diva-127502ISBN: 978-91-7685-821-9 (print)OAI: oai:DiVA.org:liu-127502DiVA: diva2:924500
Public defence
2016-06-03, Berzeliussalen, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2016-04-28 Created: 2016-04-28 Last updated: 2016-04-28Bibliographically approved
List of papers
1. TRIF adaptor signaling is important in abdominal aortic aneurysm formation
Open this publication in new window or tab >>TRIF adaptor signaling is important in abdominal aortic aneurysm formation
Show others...
2015 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 241, no 2, 561-568 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Abdominal aortic aneurysm (AAA) is characterized by inflammation, loss of smooth muscle cells (SMCs), and degradation of the extracellular matrix in the vessel wall. Innate immune receptors such as Toll-like receptors (TLRs) were recently shown to regulate immunological processes leading to the formation and progression of atherosclerotic plaques as well as to other cardiovascular pathologies. Our aim was to investigate whether blockage of TLR signaling, under the control of TIR domain-containing adaptor protein including IFN-beta (TRIF), could inhibit the inflammatory response and AAA development in mice. Results: In human AAA, an increased TLR3 and TLR4 expression in association with macrophages and T lymphocytes was demonstrated with immunohistochemical analysis. Angiotensin (Ang) II-induced aneurysm formation was significantly reduced by 30% in ApoE(-/-)Trif(-/-) mice compared to ApoE(-/-) mice. Morphologically, AngII-infused ApoE(-/-)Trif(-/-) mice had a more intact cellular and extracellular matrix while ApoE(-/-) mice infused with AngII displayed an increased medial thickness associated with aortic dissection, thrombus formation, and a more disorganized vessel wall. Gene expression analysis of the abdominal aorta revealed a profound decrease of the inflammatory genes CD68 (P less than 0.05), CD11b (P less than 0.05), and TNF-alpha (P less than 0.05) and the protease gene MMP-12 (P less than 0.01) in ApoE(-/-)Trif(-/-) mice compared to ApoE(-/-) mice infused with AngII. Conclusion: Our results suggest that signaling through TRIF is important for the inflammatory response of AngII-induced AAA and that blockage of the TRIF pathway reduces vascular inflammation and protects against AAA formation. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.

Place, publisher, year, edition, pages
ELSEVIER IRELAND LTD, 2015
Keyword
Vascular disease; Inflammation; Toll-like receptor; Angiontensin II
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-121438 (URN)10.1016/j.atherosclerosis.2015.06.014 (DOI)000360100700035 ()26100679 (PubMedID)
Note

Funding Agencies|Swedish Research Council [K2013-99X-22231-01-5]

Available from: 2015-09-18 Created: 2015-09-18 Last updated: 2017-12-04
2. Imatinib treatment attenuates growth and inflammation of angiotensin II induced abdominal aortic aneurysm
Open this publication in new window or tab >>Imatinib treatment attenuates growth and inflammation of angiotensin II induced abdominal aortic aneurysm
Show others...
2016 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 249, 101-109 p.Article in journal (Refereed) Published
Abstract [en]

AbstractBackground Abdominal aortic aneurysm (AAA) is characterized by vascular remodeling with increased infiltration of inflammatory cells and apoptosis/modulation of vascular smooth muscle cells (SMCs). Imatinib is a selective inhibitor of several tyrosine kinases, including PDGF receptors, Abl, and c-kit. The objective of this study was to characterize the potential protective role of imatinib on AAA development and the molecular mechanisms involved. Methods Male ApoE−/− mice were infused with angiotensin (Ang) II (1000 ng/kg/min) for 4 weeks to induce AAA or saline as controls. Daily treatment with 10 mg/kg imatinib, or tap water as control, was provided via gavage for 4 weeks. Results Treatment with imatinib was found to decrease the aortic diameter and vessel wall thickness, mediated by multiple effects. Imatinib treatment in AngII infused mice resulted in a reduced cellular infiltration of CD3ε positive T lymphocytes by 86% and reduced gene expression of mast cell chymase by 50% compared with AngII infused mice lacking imatinib. Gene expression analysis of SMC marker SM22α demonstrated an increase by 48% together with a more intact medial layer after treatment with imatinib as evaluated with SM22α immunostaining. Conclusion Present findings highlight the importance of tyrosine kinase pathways in the development of AAA. Our results show, that imatinib treatment inhibits essential mast cell, T lymphocyte and SMC mediated processes in experimental AAA. Thus, our results support the idea that tyrosine kinase inhibitors may be useful in the treatment of pathological vascular inflammation and remodeling in conditions like AAA.

Keyword
Abdominal aortic aneurysm, Vascular inflammation, Imatinib, Angiotensin II
National Category
Cell and Molecular Biology Physiology
Identifiers
urn:nbn:se:liu:diva-127501 (URN)10.1016/j.atherosclerosis.2016.04.006 (DOI)000376505800016 ()27085160 (PubMedID)
Available from: 2016-04-28 Created: 2016-04-28 Last updated: 2017-11-30Bibliographically approved
3. Inflammatory cells, ceramides, and expression of proteases in perivascular adipose tissue adjacent to human abdominal aortic aneurysms
Open this publication in new window or tab >>Inflammatory cells, ceramides, and expression of proteases in perivascular adipose tissue adjacent to human abdominal aortic aneurysms
Show others...
2017 (English)In: Journal of Vascular Surgery, ISSN 0741-5214, E-ISSN 1097-6809, Vol. 65, no 4, 1171- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Abdominal aortic aneurysm (AAA) is a deadly irreversible weakening and distension of the abdominal aortic wall. The pathogenesis of AAA remains poorly understood. Investigation into the physical and molecular characteristics of perivascular adipose tissue (PVAT) adjacent to AAA has not been done before and is the purpose of this study.

METHODS AND RESULTS: Human aortae, periaortic PVAT, and fat surrounding peripheral arteries were collected from patients undergoing elective surgical repair of AAA. Control aortas were obtained from recently deceased healthy organ donors with no known arterial disease. Aorta and PVAT was found in AAA to larger extent compared with control aortas. Immunohistochemistry revealed neutrophils, macrophages, mast cells, and T-cells surrounding necrotic adipocytes. Gene expression analysis showed that neutrophils, mast cells, and T-cells were found to be increased in PVAT compared with AAA as well as cathepsin K and S. The concentration of ceramides in PVAT was determined using mass spectrometry and correlated with content of T-cells in the PVAT.

CONCLUSIONS: Our results suggest a role for abnormal necrotic, inflamed, proteolytic adipose tissue to the adjacent aneurysmal aortic wall in ongoing vascular damage.

National Category
Surgery Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:liu:diva-126051 (URN)10.1016/j.jvs.2015.12.056 (DOI)000402625400035 ()26960947 (PubMedID)
Available from: 2016-03-11 Created: 2016-03-11 Last updated: 2017-06-26

Open Access in DiVA

fulltext(1241 kB)96 downloads
File information
File name FULLTEXT01.pdfFile size 1241 kBChecksum SHA-512
581982d602fc6636da55cf3bf2fd00088c3ae95c2ef3438f1764a215d94175ad4dd36b457fa738bb1f6c55fb961664af054a05845699855af9dddf1717ac7681
Type fulltextMimetype application/pdf
omslag(155 kB)16 downloads
File information
File name COVER01.pdfFile size 155 kBChecksum SHA-512
0d85195cde9d30ede5febbfc0bbcefe32d99903c4eaa07381320ae2db44ee2d92b3d8d9fc690b06c5525cf5f912860e785e81cbde18f345ec94780942e692705
Type coverMimetype application/pdf

Other links

Publisher's full text

Authority records BETA

Vorkapić, Emina

Search in DiVA

By author/editor
Vorkapić, Emina
By organisation
Division of Drug ResearchFaculty of Medicine and Health Sciences
Medicinal ChemistryMedical BiotechnologyBiochemistry and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 96 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
isbn
urn-nbn

Altmetric score

doi
isbn
urn-nbn
Total: 869 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf