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Wågsäter, Dick
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Publications (10 of 53) Show all publications
Folkesson, M., Vorkapic, E., Gulbins, E., Japtok, L., Kleuser, B., Welander, M., . . . Wågsäter, D. (2017). Inflammatory cells, ceramides, and expression of proteases in perivascular adipose tissue adjacent to human abdominal aortic aneurysms. Journal of Vascular Surgery, 65(4), 1171
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
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2017 (English)In: Journal of Vascular Surgery, ISSN 0741-5214, E-ISSN 1097-6809, Vol. 65, no 4, p. 1171-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: 2018-05-07
Folkesson, M., Sadowska, N., Vikingsson, S., Karlsson, M., Carlhäll, C.-J., Länne, T., . . . Jensen, L. (2016). Differences in cardiovascular toxicities associated with cigarette smoking and snuff use revealed using novel zebrafish models. Biology Open, 5(7), 970-978
Open this publication in new window or tab >>Differences in cardiovascular toxicities associated with cigarette smoking and snuff use revealed using novel zebrafish models
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2016 (English)In: Biology Open, ISSN 2046-6390, Vol. 5, no 7, p. 970-978Article in journal (Refereed) Published
Abstract [en]

Tobacco use is strongly associated with cardiovascular disease and the only avoidable risk factor associated with development of aortic aneurysm. While smoking is the most common form of tobacco use, snuff and other oral tobacco products are gaining popularity, but research on potentially toxic effects of oral tobacco use has not kept pace with the increase in its use. Here, we demonstrate that cigarette smoke and snuff extracts are highly toxic to developing zebrafish embryos. Exposure to such extracts led to a palette of toxic effects including early embryonic mortality, developmental delay, cerebral hemorrhages, defects in lymphatics development and ventricular function, and aneurysm development. Both cigarette smoke and snuff were more toxic than pure nicotine, indicating that other compounds in these products are also associated with toxicity. While some toxicities were found following exposure to both types of tobacco product, other toxicities, including developmental delay and aneurysm development, were specifically observed in the snuff extract group, whereas cerebral hemorrhages were only found in the group exposed to cigarette smoke extract. These findings deepen our understanding of the pathogenic effects of cigarette smoking and snuff use on the cardiovascular system and illustrate the benefits of using zebrafish to study mechanisms involved in aneurysm development.

Place, publisher, year, edition, pages
Company of Biologists, 2016
Keywords
Aneurysm; Aorta; Cardiovascular; Snuff; Tobacco; Zebrafish
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:liu:diva-130706 (URN)10.1242/bio.018812 (DOI)000380569100010 ()27334697 (PubMedID)
Note

The Jensen laboratory is supported by grants from Svenska Sallskapet for Medicinsk Forskning [grant F14-0021], Linkopings Universitet, Eva och Oscar Ahrens Stiftelse, Ollie och Elof Ericssons Stiftelse, Carmen och Bertil Ragners Stiftelse, Gosta Fraenkels Stiftelse, Ake Wibergs Stiftelse, Lions Forskningsfond, Karin Sandbergs Stiftelse, Cancerfonden, Karolinska Institutet's Stiftelser och Fonder and Vetenskapsradet [grant 2015-06271].

Available from: 2016-08-21 Created: 2016-08-21 Last updated: 2018-03-19
Gacic, J., Vorkapic, E., Slind Olsen, R., Söderberg, D., Gustafsson, T., Geffers, R., . . . Wågsäter, D. (2016). Imatinib reduces cholesterol uptake and matrix metalloproteinase activity in human THP-1 macrophages. Pharmacological Reports, 68(1), 1-6
Open this publication in new window or tab >>Imatinib reduces cholesterol uptake and matrix metalloproteinase activity in human THP-1 macrophages
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2016 (English)In: Pharmacological Reports, ISSN 1734-1140, E-ISSN 2299-5684, Vol. 68, no 1, p. 1-6Article in journal (Refereed) Published
Abstract [en]

Background: Imatinib mesylate (Glivec, formerly STI-571) is a selective tyrosine kinase inhibitor used for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. However, there are reports suggesting that imatinib could be atheroprotective by lowering plasma low-density lipoprotein (LDL). Aim: To investigate the potential inhibitory effect of imatinib on cholesterol uptake in human macrophages as well as its effect on matrix metalloproteinase (MMP) activity. Methods and results: Uptake of fluorescence-labeled LDL was analyzed using flow cytometry. Macrophages treated with imatinib showed a 23.5%, 27%, and 15% decrease in uptake of native LDL (p < 0.05), acetylated LDL (p < 0.01), and copper-modified oxidized LDL (p < 0.01), respectively. Gel based zymography showed that secretion and activity of MMP-2 and MMP-9 were inhibited by imatinib. Using GeneChip Whole Transcript Expression array analysis, no obvious gene candidates involved in the mechanisms of cholesterol metabolism or MMP regulation were found to be affected by imatinib. Instead, we found that imatinib up-regulated microRNA 155 (miR155) by 43.8% and down-regulated ADAM metallopeptidase domain 28 (ADAM28) by 41.4%. Both genes could potentially play an atheroprotective role and would be interesting targets in future studies. Conclusion: Our results indicate that imatinib causes post-translational inhibition with respect to cholesterol uptake and regulation of MMP-2 and MMP-9. More research is needed to further evaluate the role of imatinib in the regulation of other genes and processes. (c) 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.

Place, publisher, year, edition, pages
POLISH ACAD SCIENCES INST PHARMACOLOGY, 2016
Keywords
Atherosclerosis; Cholesterol; Imatinib; Macrophages
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-125158 (URN)10.1016/j.pharep.2015.05.024 (DOI)000368567800001 ()26721343 (PubMedID)
Note

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

Available from: 2016-02-15 Created: 2016-02-15 Last updated: 2018-07-18
Vorkapic, E., Dugic, E., Vikingsson, S., Roy, J., Mäyränpää, M. I., Eriksson, P. & Wågsäter, D. (2016). Imatinib treatment attenuates growth and inflammation of angiotensin II induced abdominal aortic aneurysm. Atherosclerosis, 249, 101-109
Open this publication in new window or tab >>Imatinib treatment attenuates growth and inflammation of angiotensin II induced abdominal aortic aneurysm
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2016 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 249, p. 101-109Article 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.

Keywords
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: 2018-01-10Bibliographically approved
Slind Olsen, R., Andersson, R. E., Zar, N., Löfgren, S., Wågsäter, D., Matussek, A. & Dimberg, J. (2016). Prognostic significance of PLA2G4C gene polymorphism in patients with stage II colorectal cancer.. Acta Oncologica, 55(4), 474-479
Open this publication in new window or tab >>Prognostic significance of PLA2G4C gene polymorphism in patients with stage II colorectal cancer.
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2016 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, no 4, p. 474-479Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Phospholipase A2 Group IV C (PLA2G4C) catalyzes the release of certain fatty acids from phospholipids and plays a role in a range of physiological functions, such as remodeling of cell membranes and the production of prostaglandins. Furthermore, it has been proposed that PLA2G4C plays an important role in breast cancer cell chemotaxis. This study aimed to investigate the effect of a single nucleotide polymorphism (SNP) rs1549637 (T>A) of the PLA2G4C gene on the prognosis of colorectal cancer (CRC).

MATERIAL AND METHODS: Whole blood DNA was extracted from 381 patients with CRC and 618 controls, and a TaqMan SNP genotyping assay was used to determine the distribution of the genotypes. Cancer-specific and disease-free survival was analyzed by Kaplan-Meier graphs and by uni- and multivariable Cox regression.

RESULTS: The cancer-specific survival differed between the genotypes (p = 0.019) and the carriers of the A allele were associated with the highest risk of CRC death, with a hazard ratio (HR) of 1.72 [95% confidence interval (CI) 1.17-2.53, p = 0.006] compared with homozygous carriers of the T allele. This increased mortality in the carriers with the allele A was especially marked in stage II with an HR of 3.84 (95% CI 1.51-9.78, p = 0.005).

CONCLUSION: The A allele in PLA2G4C SNP (rs1549637) is associated with a worse prognosis in patients with CRC, especially in stage II disease, and it could be a potential prognostic biomarker in the planning of individual adjuvant therapy in stage II patients.

Place, publisher, year, edition, pages
Taylor & Francis Group, 2016
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-125986 (URN)10.3109/0284186X.2015.1073350 (DOI)000372125400012 ()26364726 (PubMedID)
Note

Funding agencies: Futurum; Academy of Healthcare; Region Jonkoping County, Sweden; Foundation of Clinical Cancer Research, Jonkoping Sweden; University College of Health Sciences, Jonkoping, Sweden

Available from: 2016-03-10 Created: 2016-03-10 Last updated: 2018-01-10
Slind Olsen, R., Lindh, M., Vorkapic, E., Andersson, R. E., Zar, N., Lofgren, S., . . . Wågsäter, D. (2015). CD93 gene polymorphism is associated with disseminated colorectal cancer. International Journal of Colorectal Disease, 30(7), 883-890
Open this publication in new window or tab >>CD93 gene polymorphism is associated with disseminated colorectal cancer
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2015 (English)In: International Journal of Colorectal Disease, ISSN 0179-1958, E-ISSN 1432-1262, Vol. 30, no 7, p. 883-890Article in journal (Refereed) Published
Abstract [en]

Cluster of differentiation 93 (CD93) is involved in apoptosis and inflammation and has a suggested role in angiogenesis, and all of which are involved in the development and dissemination of cancer. We evaluated the expression of CD93 and the association with two single nucleotide polymorphisms (SNPs), rs2749812 and rs2749817, as possible biomarkers in colorectal cancer (CRC). Tissue levels and plasma levels of CD93 were measured using an enzyme-linked immunosorbent assay (ELISA). Expression of CD93 was determined by immunohistochemistry, western blot and gene expression analysis. Genotype frequencies were established for the SNPs by real-time polymerase chain reaction (PCR), and the association with tumour stage and survival was analysed. Total CD93 levels were 82 % higher (P less than 0.001) in tumours compared to matched normal tissues. Mean levels of soluble CD93 in plasma were 30 % lower (P less than 0.001) in the patients compared to the controls. The T/T genotype of SNP rs2749817 was more common in stage IV patients, with consequently higher risk of CRC death (T/T vs. C/C and C/T; hazard ratio (HR) = 1.73, 95 % confidence interval (CI) = 1.11-2.67, P = 0.014), and was associated with a higher risk of CRC recurrence after radical operation (T/T vs. C/C and C/T; HR = 2.07, CI = 1.22-3.51, P = 0.007). We showed that the T/T genotype of SNP rs2749817 is associated with disseminated cancer at diagnosis and an increased recurrence rate after radical operation. Patients with this genotype may benefit from early identification.

Place, publisher, year, edition, pages
Springer Verlag (Germany), 2015
Keywords
Biomarker; Colorectal cancer; Genotype; Prognosis; Single nucleotide polymorphism; Survival
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-120141 (URN)10.1007/s00384-015-2247-1 (DOI)000356350900003 ()26008729 (PubMedID)
Note

Funding Agencies|Foundation of Clinical Cancer Research, Jonkoping [110426-1]; Futurum; Academy of Healthcare; County Council of Jonkoping [FUTURUM-105891]; FORSS, the Research Council of Southeastern Sweden [FORSS-373251]

Available from: 2015-07-14 Created: 2015-07-13 Last updated: 2017-12-04
Alehagen, U., Vorkapic, E., Ljungberg, L., Länne, T. & Wågsäter, D. (2015). Gender difference in adiponectin associated with cardiovascular mortality. BMC Medical Genetics, 16(9)
Open this publication in new window or tab >>Gender difference in adiponectin associated with cardiovascular mortality
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2015 (English)In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 16, no 9Article in journal (Refereed) Published
Abstract [en]

Background: It is important to identify cardiovascular diseases in patients at high risk. To include genetics into routine cardiological patients has therefore been discussed recently. We wanted to evaluate the association between high-molecular weight adiponectin and cardiovascular risk, and secondly in the same population evaluate if specific genotype differences regarding risk could be observed, and thirdly if gender differences could be seen. Method: Four hundred seventy-six elderly participants recruited from a rural community were included. All participants underwent a clinical examination, echocardiography, and blood sampling and the single nucleotide polymorphism (SNP) (rs266729) of adiponectin was analysed. Follow-up time was 6.7 years. Results: Those with high serum concentration of adiponectin had a more 2 fold increased cardiovascular risk, and it might be that females exhibits even higher risk where a more than 5 fold increased risk could be seen. The result could be demonstrated even in a multivariate model adjusting for well-known clinical risk factors. However, as the sample size was small the gender differences should be interpreted with caution. In the genotype evaluation the C/C carriers of the female group had a more than 9-fold increased risk of cardiovascular mortality, however the confidence interval was wide. Such genotype difference could not be found in the male group. Conclusion: High level of adiponectin was associated with increased cardiovascular risk. Also a gender difference in the genotype evaluation could be seen where the C/C carriers obtained higher risk in the female group but not in the male group. Thus, in order to identify patients at risk early, genetic analyses may add to the armamentarium used in the clinical routine. However, information should be regarded as hypothesis generating as the sample size was small and should stimulate further research in individualized cardiovascular prevention and treatment.

Place, publisher, year, edition, pages
BioMed Central / Springer Verlag (Germany), 2015
Keywords
Genotypes; Gender; Prognosis
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-120043 (URN)10.1186/s12881-015-0187-9 (DOI)000356038000001 ()26068642 (PubMedID)
Note

Funding Agencies|County Council of Ostergotland; University of Linkoping, Linkoping, Sweden; Swedish Heart and Lung Foundation

Available from: 2015-07-06 Created: 2015-07-06 Last updated: 2017-12-04
Bertorello, A. M., Pires, N., Igreja, B., Joao Pinho, M., Vorkapic, E., Wågsäter, D., . . . Brion, L. (2015). Increased Arterial Blood Pressure and Vascular Remodeling in Mice Lacking Salt-Inducible Kinase 1 (SIK1). Circulation Research, 116(4), 642-U190
Open this publication in new window or tab >>Increased Arterial Blood Pressure and Vascular Remodeling in Mice Lacking Salt-Inducible Kinase 1 (SIK1)
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2015 (English)In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 116, no 4, p. 642-U190Article in journal (Refereed) Published
Abstract [en]

Rationale: In human genetic studies a single nucleotide polymorphism within the salt-inducible kinase 1 (SIK1) gene was associated with hypertension. Lower SIK1 activity in vascular smooth muscle cells (VSMCs) leads to decreased sodium-potassium ATPase activity, which associates with increased vascular tone. Also, SIK1 participates in a negative feedback mechanism on the transforming growth factor-beta 1 signaling and downregulation of SIK1 induces the expression of extracellular matrix remodeling genes. Objective: To evaluate whether reduced expression/activity of SIK1 alone or in combination with elevated salt intake could modify the structure and function of the vasculature, leading to higher blood pressure. Methods and Results: SIK1 knockout (sik1(-/-)) and wild-type (sik1(+/+)) mice were challenged to a normal-or chronic high-salt intake (1% NaCl). Under normal-salt conditions, the sik1(-/-) mice showed increased collagen deposition in the aorta but similar blood pressure compared with the sik1(+/+) mice. During high-salt intake, the sik1+/+ mice exhibited an increase in SIK1 expression in the VSMCs layer of the aorta, whereas the sik1(-/-) mice exhibited upregulated transforming growth factor-beta 1 signaling and increased expression of endothelin-1 and genes involved in VSMC contraction, higher systolic blood pressure, and signs of cardiac hypertrophy. In vitro knockdown of SIK1 induced upregulation of collagen in aortic adventitial fibroblasts and enhanced the expression of contractile markers and of endothelin-1 in VSMCs. Conclusions: Vascular SIK1 activation might represent a novel mechanism involved in the prevention of high blood pressure development triggered by high-salt intake through the modulation of the contractile phenotype of VSMCs via transforming growth factor-beta 1-signaling inhibition.

Place, publisher, year, edition, pages
American Heart Association, 2015
Keywords
endothelin-1; muscle, smooth, vascular; SIK1 protein, human; vascular remodeling
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-115818 (URN)10.1161/CIRCRESAHA.116.304529 (DOI)000349804900014 ()25556206 (PubMedID)
Note

Funding Agencies|Swedish Research Council [10860]; Swedish Heart and Lung Foundation [20120227]; AFA Insurance Sweden [090246]; Fundacao para a Ciencia e a Tecnologia [PIC/IC/83204/2007]

Available from: 2015-03-20 Created: 2015-03-20 Last updated: 2017-12-04
Folkesson, M., Li, C., Frebelius, S., Swedenborg, J., Wågsäter, D., Jon Williams, K., . . . Liu, M.-L. (2015). Proteolytically active ADAM10 and ADAM17 carried on membrane microvesicles in human abdominal aortic aneurysms. Thrombosis and Haemostasis, 114(6), 1165-1174
Open this publication in new window or tab >>Proteolytically active ADAM10 and ADAM17 carried on membrane microvesicles in human abdominal aortic aneurysms
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2015 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 114, no 6, p. 1165-1174Article in journal (Refereed) Published
Abstract [en]

The intraluminal thrombus (ILT) of human abdominal aortic aneurysm (AAA) has been suggested to damage the underlying aortic wall, but previous work found scant activity of soluble proteases in the abluminal layer of the ILT, adjacent to the aneurysm. We hypothesised that transmembrane proteases carried by membrane microvesicles (MV) from dying cells remain active in the abluminal ILT. ILTs and AAA segments collected from 21 patients during surgical repair were assayed for two major transmembrane proteases, ADAM10 (a disintegrin and metalloprotease-10) and ADAM17. We also exposed cultured cells to tobacco smoke and assessed ADAM10 and ADAM17 expression and release on MVs. Immunohistochemistry showed abundant ADAM10 and ADAM17 protein in the ILT and underlying aneurysmal aorta. Domain-specific antibodies indicated both transmembrane and shed ADAM17. Importantly, ADAM10 and ADAM 17 in the abluminal ILT were enzymatically active. Electron microscopy of abluminal ILT and aortic wall showed MVs with ADAM10 and ADAM17. By flow cytometry, ADAM-positive microvesicles from abluminal ILT carried the neutrophil marker CD66, but not the platelet marker CD61. Cultured HL60 neutrophils exposed to tobacco smoke extract showed increased ADAM10 and ADAM17 content, cleavage of these molecules into active forms, and release of MVs carrying mature ADAM10 and detectable ADAM17. In conclusion, our results implicate persistent, enzymatically active ADAMs on MVs in the abluminal ILT, adjacent to the aneurysmal wall. The production of ADAM10- and ADAM17-positive MVs from smoke-exposed neutrophils provides a novel molecular mechanism for the vastly accelerated risk of AAA in smokers.

Place, publisher, year, edition, pages
SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN, 2015
Keywords
Abdominal aortic aneurysm; ADAM10; ADAM17; intraluminal thrombus; A disintegrin and matrix metalloproteinase; membrane-bound protease; microparticles; microvesicles
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-123793 (URN)10.1160/TH14-10-0899 (DOI)000365769200010 ()26422658 (PubMedID)
Available from: 2016-01-11 Created: 2016-01-11 Last updated: 2017-11-30
Vorkapic, E., Lundberg, A. M., Mayranpaa, M. I., Eriksson, P. & Wågsäter, D. (2015). TRIF adaptor signaling is important in abdominal aortic aneurysm formation. Atherosclerosis, 241(2), 561-568
Open this publication in new window or tab >>TRIF adaptor signaling is important in abdominal aortic aneurysm formation
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2015 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 241, no 2, p. 561-568Article 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
Keywords
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
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