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Imatinib treatment attenuates growth and inflammation of angiotensin II induced abdominal aortic aneurysm
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
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2016 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 249, 101-109 p.Article in journal (Refereed) Published
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Text
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.

Place, publisher, year, edition, pages
2016. Vol. 249, 101-109 p.
Keyword [en]
Abdominal aortic aneurysm, Vascular inflammation, Imatinib, Angiotensin II
National Category
Cell and Molecular Biology Physiology
Identifiers
URN: urn:nbn:se:liu:diva-127501DOI: 10.1016/j.atherosclerosis.2016.04.006ISI: 000376505800016PubMedID: 27085160OAI: oai:DiVA.org:liu-127501DiVA: diva2:924471
Available from: 2016-04-28 Created: 2016-04-28 Last updated: 2017-11-30Bibliographically approved
In thesis
1. Targeting vascular remodeling in abdominal aortic aneurysm: To identify novel treatment strategies and drug candidates
Open this publication in new window or tab >>Targeting vascular remodeling in abdominal aortic aneurysm: To identify novel treatment strategies and drug candidates
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:nbn:se:liu:diva-127502 (URN)10.3384/diss.diva-127502 (DOI)978-91-7685-821-9 (ISBN)
Public defence
2016-06-03, Berzeliussalen, Campus US, Linköping, 13:00 (English)
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Available from: 2016-04-28 Created: 2016-04-28 Last updated: 2016-04-28Bibliographically approved

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