| 1. |
- Rattik, Sara, et al.
(author)
-
B cells treated with CTB-p210 acquire a regulatory phenotype in vitro and reduce atherosclerosis in apolipoprotein E deficient mice
- 2018
-
In: Vascular Pharmacology. - : Elsevier BV. - 1537-1891. ; 111, s. 54-61
-
Journal article (peer-reviewed)abstract
- Objective: Intranasal immunization with a fusion protein of the ApoB100-derived peptide p210 and the cholera toxin B subunit (CTB-p210) has previously been shown to induce mucosal tolerance and reduce atherosclerosis development, but the exact mode of action remains to be elucidated. Recent studies have indicated an important role for B cells in mucosal tolerance, in particular by induction of regulatory B (Bregs) and T cells (Tregs). In this study, we aimed to investigate if transfer of B cells pulsed with CTB-p210 can protect against atherosclerosis. Method and results: First, we studied if CTB-p210 can induce Bregs and Tregs in vitro. After pulsing B cells from Apob(tm2gy)ldlr(-/-) or Apoe(-/-) mice with CTB-p210 for 1 h and co-culturing them with naive T cells for 48 h, we observed increased expression of membrane bound TGF beta/latency-associated peptide (mTGF beta/LAP) on B cells and an increased proportion of CD25(hi)FoxP3(+) Tregs. Adoptive transfer of B cells pulsed with CTB-p210 into high-fat diet-fed Apoe(-/-) mice at 8, 10 and 12 weeks of age, reduced the plaque area in the aorta at 20 weeks of age as compared with control-treated (CTB-pOVA treated B cells or PBS) mice. Moreover, mice receiving p210-CTB treated B cells had increased levels of anti-p210 IgG antibodies. Conclusion: Our observations suggest that CTB-p210 pulsed B cells acquire a regulatory phenotype and induce Tregs in vitro. Adoptive transfer of CTB-p210, but not control-treated, B cells into Apoe(-/-) mice decreased atherosclerosis development.
|
|
| 2. |
- Yao Mattisson, Ingrid, et al.
(author)
-
Immune responses against oxidized LDL as possible targets for prevention of atherosclerosis in systemic lupus erythematosus
- 2021
-
In: Vascular Pharmacology. - : Elsevier BV. - 1537-1891. ; 140
-
Journal article (peer-reviewed)abstract
- Patients suffering from systemic lupus erythematosus (SLE) are at increased risk of developing cardiovascular disease (CVD) and traditional therapies including statins provide insufficient protection. Impaired removal of apoptotic material is a common pathogenic mechanism in both SLE and atherosclerosis and is considered to be a key factor in the development of autoimmunity. Since oxidized LDL and apoptotic material bind to the same receptors, we aimed to investigate if targeting the oxidized LDL autoimmunity can affect atherosclerosis in SLE. To investigate the possible role of oxidized LDL autoimmunity in the accelerated atherosclerosis associated with SLE we used a hypercholesterolemic SLE mouse model (B6.lpr.ApoE−/− mice). Promoting LDL tolerance through mucosal immunization with an apolipoprotein B-100 peptide p45 (amino acids 661–680) and cholera toxin B-subunit fusion protein increased regulatory T cells and B cells in mesenteric lymph nodes and reduced plaque development in the aorta by 33%. Treatment with the oxidized LDL-specific antibody Orticumab reduced aortic atherosclerosis by 43%, subvalvular plaque area by 50% and the macrophage content by 31%. The present study provides support for oxLDL as a possible target for prevention of cardiovascular complications in SLE. © 2021 The Author(s)
|
|
| 3. |
|
|
| 4. |
- Beser, Jessica, et al.
(author)
-
Seroprevalence of SARS-CoV-2 in Sweden, April 26 to May 9, 2021
- 2022
-
In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 12:1
-
Journal article (peer-reviewed)abstract
- A national point seroprevalence study of SARS-CoV-2 was conducted in Sweden in April–May 2021. In total, 2860 individuals 3 to 90 years old from a probability-based web panel were included. Results showed that an estimated 32.6% of the population in Sweden had detectable levels of antibodies, and among non-vaccinated 20.1% had detectable levels of antibodies. We tested for differences in seroprevalence between age groups and by sex and estimated seroprevalence among previously infected participants by time since reporting.
|
|
| 5. |
|
|
| 6. |
- Choquet, Isabelle, 1965-, et al.
(author)
-
Clogging and lump formation during atmospheric plasma spraying with powder injection downstream the plasma gun
- 2007
-
In: Journal of thermal spray technology (Print). - : Springer Science and Business Media LLC. - 1059-9630 .- 1544-1016. ; 16:4, s. 512-523
-
Journal article (peer-reviewed)abstract
- This study aimed to numerically and experimentally investigate lump formation during atmospheric plasma spraying with powder injection downstream the plasma gun exit. A first set of investigations was focused on the location and orientation of the powder port injector. It turned out impossible to keep the coating quality while avoiding lumps by simply moving the powder injector. A new geometry of the powder port ring holder was designed and optimized to prevent nozzle clogging, and lump formation using a gas screen. This solution was successfully tested for applications with Ni-5wt.%Al and ZrO2-7wt.%Y2O3 powders used in production. The possible secondary effect of plasma jet shrouding by the gas screen, and its consequence on powder particles prior to impact was also studied.
|
|
| 7. |
- Engelbertsen, Daniel, et al.
(author)
-
IL-1R and MyD88 signalling in CD4+ T cells promote Th17 immunity and atherosclerosis
- 2018
-
In: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 114:1, s. 180-187
-
Journal article (peer-reviewed)abstract
- The role of CD4+ T cells in atherosclerosis has been shown to be dependent on cytokine cues that regulate lineage commitment into mature T helper sub-sets. In this study, we tested the roles of IL-1R1 and MyD88 signalling in CD4+ T cells in atherosclerosis. Methods and results We transferred apoe-/-myd88\+/\+ or apoe-/-myd88-/- CD4+ T cells to T-A nd B-cell-deficient rag1-/-apoe-/- mice fed high fat diet. Mice given apoe-/-myd88-/- CD4+ T cells exhibited reduced atherosclerosis compared with mice given apoe-/-myd88\+/\+ CD4+ T cells. CD4+ T cells from apoe-/-myd88-/- produced less IL-17 but similar levels of IFN-c. Treatment of human CD4+ T cells with a MyD88 inhibitor inhibited IL-17 secretion in vitro. Transfer of il1r1-/- CD4+ T cells recapitulated the phenotype seen by transfer of myd88-/- CD4+ T cells with reduced lesion development and a reduction in Th17 and IL-17 production compared with wild type CD4+ T cell recipients. Relative collagen content of lesions was reduced in mice receiving il1r1-/- CD4+ T cells. Conclusion We demonstrate that both IL1R and MyD88 signalling in CD4+ T cells promote Th17 immunity, plaque growth and may regulate plaque collagen levels.
|
|
| 8. |
- Engelbertsen, Daniel, et al.
(author)
-
T-Helper 2 Immunity Is Associated With Reduced Risk of Myocardial Infarction and Stroke.
- 2013
-
In: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636.
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: Experimental studies in mice have attributed T-helper (Th) 1 and Th2 cells important roles in atherosclerosis, but the clinical importance of these cells in cardiovascular disease (CVD) remains to be clarified. Here, we investigated associations between Th1 and Th2 cells, carotid intima-media thickness, and cardiovascular risk. METHODS AND RESULTS: Blood drawn at baseline and incident cardiovascular events during 15-year follow-up were assessed in 700 participants. Baseline Th1 (CD3(+)CD4(+)interferon-γ(+)) and Th2 (CD3(+)CD4(+)IL-4(+)) cells were analyzed by flow cytometry, and cytokine-release from activated mononuclear leukocytes was measured by multiplex technology. High numbers of Th2 cells were independently associated with decreased mean common carotid intima-media thickness. High numbers of Th2 cells were also independently associated with a reduced risk of acute myocardial infarction in women (hazard ratio, 0.19; 95% confidence interval, 0.06-0.56; P=0.002 for the highest versus the lowest tertile of Th2 cells). Moreover, release of the Th2 cytokine IL-4 from activated mononuclear leukocytes was independently associated with a reduced risk of CVD. No independent associations between Th1 cells and carotid intima-media thickness or CVD risk were found. CONCLUSIONS: Our observations provide the first clinical evidence for a protective role of Th2 immunity in CVD. They also suggest this protection is more prominent in women than in men. In spite of convincing evidence from experimental studies, we found no support for a role of Th1 immunity in CVD.
|
|
| 9. |
- Gonçalves, Isabel, et al.
(author)
-
Association between renin and atherosclerotic burden in subjects with and without type 2 diabetes
- 2016
-
In: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 16:1, s. 1-10
-
Journal article (peer-reviewed)abstract
- Background: Activation of the renin-angiotensin-aldosterone-system (RAAS) has been proposed to contribute to development of vascular complications in type 2 diabetes (T2D). The aim of the present study was to determine if plasma renin levels are associated with the severity of vascular changes in subjects with and without T2D. Methods: Renin was analyzed by the Proximity Extension Assay in subjects with (n = 985) and without (n = 515) T2D participating in the SUMMIT (SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools) study and in 205 carotid endarterectomy patients. Vascular changes were assessed by determining ankle-brachial pressure index (ABPI), carotid intima-media thickness (IMT), carotid plaque area, pulse wave velocity (PWV) and the reactivity hyperemia index (RHI). Results: Plasma renin was elevated in subjects with T2D and demonstrated risk factor-independent association with prevalent cardiovascular disease both in subjects with and without T2D. Renin levels increased with age, body mass index, HbA1c and correlated inversely with HDL. Subjects with T2D had more severe carotid disease, increased arterial stiffness, and impaired endothelial function. Risk factor-independent associations between renin and APBI, bulb IMT, carotid plaque area were observed in both T2D and non-T2D subjects. These associations were independent of treatment with RAAS inhibitors. Only weak associations existed between plasma renin and the expression of pro-inflammatory and fibrous components in plaques from 205 endarterectomy patients. Conclusions: Our findings provide clinical evidence for associations between systemic RAAS activation and atherosclerotic burden and suggest that this association is of particular importance in T2D.
|
|
| 10. |
- Grönberg, Caitríona, et al.
(author)
-
Recent advances on CD4+ T cells in atherosclerosis and its implications for therapy
- 2017
-
In: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 816, s. 58-66
-
Journal article (peer-reviewed)abstract
- Atherosclerosis is an arterial inflammatory disease and the primary cause of cardiovascular disease. T helper (Th) cells are an important part in atherosclerotic plaque as they can be either disease promoting or protective. A body of evidence points to a pro-atherosclerotic role of Th1 cells, whereas the role of Th2, Th17 and iNKT cells seems more complex and dependent on surrounding factors, including the developmental stage of the disease. Opposed to Th1 cells, there is convincing support for an anti-atherogenic role of Tregs. Recent data identify the plasticity of Th cells as an important challenge in understanding the functional role of different Th cell subsets in atherosclerosis. Much of the knowledge of Th cell function in atherosclerosis is based on findings from experimental models and translating this into human disease is challenging. Targeting Th cells and/or their specific cytokines represents an attractive option for future therapy against atherosclerosis, although the benefits and the risk of modulation of Th cells with these novel drug targets must first be carefully assessed.
|
|
| 11. |
- Knutsson, Anki, et al.
(author)
-
Treatment with a GnRH receptor agonist, but not the GnRH receptor antagonist degarelix, induces atherosclerotic plaque instability in ApoE-/- mice
- 2016
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
-
Journal article (peer-reviewed)abstract
- Androgen-deprivation therapy (ADT) for prostate cancer has been associated with increased risk for development of cardiovascular events and recent pooled analyses of randomized intervention trials suggest that this primarily is the case for patients with pre-existing cardiovascular disease treated with gonadotropin-releasing hormone receptor (GnRH-R) agonists. In the present study we investigated the effects of the GnRH-R agonist leuprolide and the GnRH-R antagonist degarelix on established atherosclerotic plaques in ApoE-/- mice. A shear stress modifier was used to produce both advanced and more stable plaques in the carotid artery. After 4 weeks of ADT, increased areas of necrosis was observed in stable plaques from leuprolide-treated mice (median and IQR plaque necrotic area in control, degarelix and leuprolide-treated mice were 0.6% (IQR 0-3.1), 0.2% (IQR 0-4.4) and 11.0% (IQR 1.0-19.8), respectively). There was also evidence of increased inflammation as assessed by macrophage immunohistochemistry in the plaques from leuprolide-treated mice, but we found no evidence of such changes in plaques from control mice or mice treated with degarelix. Necrosis destabilizes plaques and increases the risk for rupture and development of acute cardiovascular events. Destabilization of pre-existing atherosclerotic plaques could explain the increased cardiovascular risk in prostate cancer patients treated with GnRH-R agonists.
|
|
| 12. |
|
|
| 13. |
- Kolbus, Daniel, et al.
(author)
-
CD8+ T cell activation predominate early immune responses to hypercholesterolemia in Apoe-/- mice.
- 2010
-
In: BMC Immunology. - : Springer Science and Business Media LLC. - 1471-2172. ; 11
-
Journal article (peer-reviewed)abstract
- It is well established that adaptive immune responses induced by hypercholesterolemia play an important role in the development of atherosclerosis, but the pathways involved remain to be fully characterized. In the present study we assessed immune responses to hypercholesterolemia induced by feeding Apoe-/- mice a high-fat diet for 4 or 8 weeks.
|
|
| 14. |
- Kolbus, Daniel, et al.
(author)
-
Immunization with cationized BSA inhibits progression of disease in ApoBec-1/LDL receptor deficient mice with manifest atherosclerosis.
- 2011
-
In: Immunobiology. - : Elsevier BV. - 1878-3279 .- 0171-2985. ; 216, s. 663-669
-
Journal article (peer-reviewed)abstract
- Immune responses against modified self-antigens generated by hypercholesterolemia play an important role in atherosclerosis identifying the immune system as a possible novel target for prevention and treatment of cardiovascular disease. It has recently been shown that these immune responses can be modulated by subcutaneous injection of adjuvant. In the present study we immunized 25-week old ApoBec-1/LDL receptor deficient mice with manifest atherosclerosis with adjuvant and two different concentrations of the carrier molecule cationized BSA (cBSA). Plasma levels of Th2-induced apolipoprotein B (apoB)/IgG1 immune complexes were increased in the cBSA immunized groups verifying induction of immunity against a self-antigen. Mice were sacrificed at 36 weeks of age and atherosclerosis was monitored by en face Oil red O staining of the aorta. Immunization with 100μg cBSA inhibited plaque progression, whereas the lower dose (50μg) did not. In addition, the higher dose induced a more stable plaque phenotype, indicated by a higher content of collagen and less macrophages and T cells in the plaques. Moreover, there was an increased ratio of Foxp3(+)/Foxp3(-) T cells in the circulation suggesting activation of a regulatory T cell response. In conclusion, we show that immunization with cBSA induces an immune response against apoB as well as an activation of Treg cells. This was associated with development of a more stable plaque phenotype and reduced atherosclerosis progression.
|
|
| 15. |
- Liu, Yan, et al.
(author)
-
Long crack behavior in a thermal barrier coating upon thermal shock loading
- 2005
-
In: Journal of Thermal Spray Technology. - : Springer Science and Business Media LLC. - 1544-1016 .- 1059-9630 .- 0000-0000. ; 14:2, s. 258-263
-
Journal article (peer-reviewed)abstract
- The behavior of macroscopic long cracks in the ceramic top coat of a thermal barrier coating (TBC) system subjected to thermal shock loading and the influence of the cracks on the coating durability were investigated experimentally and numerically. Thermal shock testing was conducted until coating failure. Comparisons were made with coating samples without macroscopic cracks. The experimental results revealed that the presence of macroscopic cracks reduces the life of the TBC. The finite-element method, with a fracture mechanics approach, was applied to analyze preexisting long cracks, and the calculations correlate well with the experimental findings. It was found that the life of the coating is reduced with crack length as well as with maximum cycle temperature. It was also found that the stress-intensity factors for long cracks are initially high and decrease with the number of temperature cycles, which indicates that rapid crack growth occurs during the first number of cycles.
|
|
| 16. |
- Lyphout, Christophe, 1981, et al.
(author)
-
Characterization of Adhesion Strength and Residual Stresses of HVOF Sprayed Inconel 718 for Aerospace Repair Applications
- 2007
-
In: Proceedings of the International Thermal Spray Conference (ITSC), Beijing, China. ; , s. 588-593
-
Conference paper (other academic/artistic)abstract
- Thermally sprayed Inconel 718 coatings have been deposited by high velocity oxy-fuel (HVOF) spraying on Inconel 718 substrates. The aim of the on-going study is to understand and control the adhesion mechanisms and the residual stress state of the deposit/substrate system, in order to build up thick coatings for maintenance purposes. The coating adhesion strength was evaluated by the standard ASTM C633 tensile test. Coating shear strength was evaluated by the recently developed prEN15340 Shear Test. A modified Layer Removal Method (MLRM) test was carried out to measure residual stresses. The work is a part of an ongoing study for evaluation of relationships between process parameters, residual stress distribution and adhesion strength.
|
|
| 17. |
|
|
| 18. |
- Markocsan, Nicolaie, et al.
(author)
-
Effect of heat treatment on low conductive thermal barrier coatings
- 2009
-
In: Proceedings of the 22nd International Conference on Surface Modification Technologies. - 9780981706511 ; , s. 139-147
-
Conference paper (peer-reviewed)abstract
- Development of Thermal Barrier Coating (TBC) systems will allow higher combustion temperature which is of interest for all manufactures since it results in higher fuel efficiency and environmentally cleaner emissions. Low thermal conductivity and long service life are the most important properties of these coatings. The objective of the work presented in this paper was to study the influence of a long-term heat treatment (i.e. 1200°C/2000h) on different characteristics of atmospheric plasma sprayed TBCs. Two zirconia feedstock materials were evaluated, namely yttria partially stabilised zirconia and dysprosia partially stabilised zirconia. Several spray conditions were designed and employed in order to achieve different coating morphologies. Microstructure analyses revealed that the coating microstructure was significantly dependent on both operating conditions and heat treatment conditions. Significant changes in coatings porosity occurred during heat treatment. The lowest thermal conductivity was reached with the dysprosia partially stabilised zirconia material. All TBC systems experienced decomposition of the metastable t´ phase during long heat treatment at 1200°C.
|
|
| 19. |
- Markocsan, Nicolaie, 1967-, et al.
(author)
-
Liquid Feedstock Plasma Spraying : An Emerging Process for Advanced Thermal Barrier Coatings
- 2017
-
In: Journal of thermal spray technology (Print). - : Springer Science and Business Media LLC. - 1059-9630 .- 1544-1016. ; 26:6, s. 1104-1114
-
Journal article (peer-reviewed)abstract
- Liquid feedstock plasma spraying (LFPS) involves deposition of ultrafine droplets of suspensions or solution precursors (typically ranging from nano- to submicron size) and permits production of coatings with unique microstructures that are promising for advanced thermal barrier coating (TBC) applications. This paper reviews the recent progress arising from efforts devoted to development of high-performance TBCs using the LFPS approach. Advancements in both suspension plasma spraying and solution precursor plasma spraying, which constitute the two main variants of LFPS, are presented. Results illustrating the different types of the microstructures that can be realized in LFPS through appropriate process parameter control, model-assisted assessment of influence of coating defects on thermo-mechanical properties and the complex interplay between pore coarsening, sintering and crystallite growth in governing thermal conductivity are summarized. The enhancement in functional performances/lifetime possible in LFPS TBCs with multilayered architectures and by incorporating new pyrochlore chemistries such as gadolinium zirconate, besides the conventional single 8 wt.% yttria-stabilized zirconia insulating ceramic layer, is specifically highlighted.
|
|
| 20. |
|
|
| 21. |
- Markocsan, Nicolaie, 1967-, et al.
(author)
-
Thermal spraying in Europe’s Nordic region
- 2007
-
In: Journal of thermal spray technology (Print). - : Springer. - 1059-9630 .- 1544-1016. ; 16:4, s. 463-464
-
Journal article (peer-reviewed)
|
|
| 22. |
- Nilsson, Jan, et al.
(author)
-
Regulatory T cells and the control of modified lipoprotein autoimmunity-driven atherosclerosis.
- 2009
-
In: Trends in Cardiovascular Medicine. - : Elsevier BV. - 1873-2615 .- 1050-1738. ; 19:8, s. 272-276
-
Journal article (peer-reviewed)abstract
- It has long been recognized that arterial inflammation plays a key role in the development of atherosclerosis. More recent evidence has suggested that this inflammation is modulated by autoimmune responses against modified self-antigens, such as oxidized low-density lipoprotein, in the vascular wall. However, the role of the immune system in atherosclerosis appears to be more complex than in classic autoimmune diseases; and a number of protective immune responses have also been identified. One of the most important of these is carried out by the regulatory T cells. Regulatory T cells inhibit the development of autoimmunity by controlling the activity of autoreactive T cells. If the function of regulatory T cells is compromised in hypercholesterolemic mouse models of atherosclerosis, the development of disease becomes much more aggressive. In this review, we will discuss the possibility that the inflammatory activity in atherosclerotic lesions depends on the balance between plaque antigen-specific proinflammatory Th1-type T cells and anti-inflammatory regulatory T cells specific for the same antigen. We will also discuss the role of hypercholesterolemia in generation of these modified self-antigens as well as ongoing research aiming to develop novel immune-modulating therapy for prevention of cardiovascular disease by targeting these processes.
|
|
| 23. |
- Nilsson, Jan, et al.
(author)
-
Vaccines against atherosclerosis.
- 2013
-
In: Expert Review of Vaccines. - : Informa UK Limited. - 1744-8395 .- 1476-0584. ; 12:3, s. 311-321
-
Research review (peer-reviewed)abstract
- Atherosclerosis is the primary cause of acute myocardial infarction and stroke. It is well established that arterial inflammation in response to accumulation and oxidation of lipoproteins in the vascular wall is the major factor responsible for the development of atherosclerosis. During recent years, it has become apparent that this vascular inflammation is modulated by a complex array of autoimmune responses against modified self-antigens in the atherosclerotic plaque and that both protective and pathogenic immune responses become activated as part of the disease process. Studies of hypercholesterolemia-induced immune activation in mouse models of atherosclerosis have demonstrated that Th1 cells contribute to disease progression while regulatory T cells are protective. It has been suggested that antigen presentation of modified self-antigens in the inflammatory environment of atherosclerotic plaques favors generation of antigen-specific Th1 cells over that of regulatory T cells, resulting in a local loss of tolerance. This concept has stimulated the development of plaque-antigen tolerogenic vaccines to dampen plaque inflammation and disease progression. A first generation of atherosclerosis vaccines based on peptides derived from apoB100 and heat shock proteins have demonstrated promising results in animal studies and are now approaching clinical testing.
|
|
| 24. |
|
|
| 25. |
- Omar, Omar, et al.
(author)
-
In vivo gene expression in response to anodically oxidized versus machined titanium implants.
- 2010
-
In: Journal of biomedical materials research. Part A. - : Wiley. - 1552-4965 .- 1549-3296. ; 92:4, s. 1552-1566
-
Journal article (peer-reviewed)abstract
- A quantitative polymerase chain reaction technique (qPCR) in combination with scanning electron microscopy was applied for the evaluation of early gene expression response and cellular reactions close to titanium implants. Anodically oxidized and machined titanium miniscrews were inserted in rat tibiae. After 1, 3, and 6 days the implants were unscrewed and the surrounding bone was retrieved using trephines. Both the implants and bone were analyzed with qPCR. A greater amount of cells, as indicated with higher expression of 18S, was detected on the oxidized surface after 1 and 6 days. Significantly higher osteocalcin (at day 6), alkaline phosphatase (at days 3 and 6), and cathepsin K (at day 3) expression was demonstrated for the oxidized surface. Higher expression of tumor necrosis factor-alpha (at day 1) and interleukin-1beta (at days 1 and 6) was detected on the machined surfaces. SEM revealed a higher amount of mesenchymal-like cells on the oxidized surface. The results show that the rapid recruitment of mesenchymal cells, the rapid triggering of gene expression crucial for bone remodeling and the transient nature of inflammation, constitute biological mechanisms for osseointegration, and high implant stability associated with anodically oxidized implants. (c) 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2009.
|
|
| 26. |
|
|
| 27. |
- Rattik, Sara, et al.
(author)
-
Elevated circulating effector memory T cells but similar levels of regulatory T cells in patients with type 2 diabetes mellitus and cardiovascular disease
- 2019
-
In: Diabetes and Vascular Disease Research. - : SAGE Publications. - 1479-1641 .- 1752-8984. ; 16:3, s. 270-280
-
Journal article (peer-reviewed)abstract
- Type 2 diabetes mellitus is associated with an elevated risk of cardiovascular disease, but the mechanism through which diabetes contributes to cardiovascular disease development remains incompletely understood. In this study, we compared the association of circulating regulatory T cells, naïve T cells, effector memory T cells or central memory T cells with cardiovascular disease in patients with and without type 2 diabetes mellitus. Percentage of circulating T cell subsets was analysed by flow cytometry in type 2 diabetes mellitus subjects with and without prevalent cardiovascular disease as well as in non-diabetic subjects with and without prevalent cardiovascular disease from the Malmö SUMMIT cohort. Subjects with type 2 diabetes mellitus had elevated percentages of effector memory T cells (CD4+CD45RO+CD62L–; 21.8% ± 11.2% vs 17.0% ± 9.2% in non-type 2 diabetes mellitus, p < 0.01) and central memory T cells (CD4+CD45RO+CD62L+; 38.0% ± 10.7% vs 36.0% ± 9.5% in non-type 2 diabetes mellitus, p < 0.01). In contrast, the frequency of naïve T cells was reduced (CD4+CD45RO–CD62L+, 35.0% ± 16.5% vs 42.9% ± 14.4% in non-type 2 diabetes mellitus, p < 0.001). The proportion of effector memory T cells was increased in type 2 diabetes mellitus subjects with cardiovascular disease as compared to those without (26.4% ± 11.5% vs 18.4% ± 10.2%, p < 0.05), while no difference in regulatory T cells was observed between these two patient groups. This study identifies effector memory T cells as a potential cellular biomarker for cardiovascular disease among subjects with type 2 diabetes mellitus, suggesting a state of exacerbated immune activation in type 2 diabetes mellitus patients with cardiovascular disease.
|
|
| 28. |
- Rattik, Sara, et al.
(author)
-
High Plasma Levels of Heparin-Binding Epidermal Growth Factor Are Associated With a More Stable Plaque Phenotype and Reduced Incidence of Coronary Events
- 2015
-
In: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 35:1, s. 222-228
-
Journal article (peer-reviewed)abstract
- Objective-Rupture of atherosclerotic plaques is the major cause of acute coronary events (CEs). Plaque destabilization is the consequence of an imbalance between inflammatory-driven degradation of fibrous tissue and smooth muscle cell-dependent tissue repair. Proinflammatory factors have been documented extensively as biomarkers of cardiovascular risk but factors that contribute to stabilization of atherosclerotic plaques have received less attention. The present study aimed to investigate whether plasma levels of the smooth muscle cell growth factor epidermal growth factor (EGF), heparin-binding-EGF (HB-EGF), and platelet-derived growth factor correlate with plaque phenotype and incidence of CEs. Approach and Results-HB-EGF, EGF and platelet-derived growth factor were measured in plasma from 202 patients undergoing carotid endarterectomy and in 384 incident CE cases and 409 matched controls recruited from the Malmo Diet and Cancer cohort. Significant positive associations were found between the plasma levels of all 3 growth factors and the collagen and elastin contents of the removed plaques. CE cases in the Malmo Diet and Cancer cohort had lower levels of HB-EGF in plasma, whereas no significant differences were found for EGF and platelet-derived growth factor. After adjusting for cardiovascular risk factors in a Cox proportional hazard model, the hazard ratio for the highest HB-EGF tertile was 0.61 (95% confidence interval, 0.47-0.82; P<0.001). Conclusions-The associations between high levels of smooth muscle cell growth factors in plasma and a more fibrous plaque phenotype as well as the association between low levels of HB-EGF and incident CEs point to a potential clinically important role for factors that contribute to plaque stabilization by stimulating smooth muscle cells.
|
|
| 29. |
- Rattik, Sara, et al.
(author)
-
IL-22 affects smooth muscle cell phenotype and plaque formation in apolipoprotein E knockout mice.
- 2015
-
In: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 242:2, s. 506-514
-
Journal article (peer-reviewed)abstract
- IL-22 is a recently discovered cytokine that belongs to the family of IL-10 related cytokines. It is produced by activated T-cells and innate lymphoid cells and has been suggested to be involved in tissue repair. As both inflammation and repair play important roles in atherosclerosis we investigated if IL-22 deficiency influences the disease process in Apoe(-/-) mice.
|
|
| 30. |
- Ström, Åsa, et al.
(author)
-
Involvement of the CD1d-Natural killer T cell pathway in neointima formation after vascular injury
- 2007
-
In: CIRCULATION RESEARCH. - 0009-7330. ; 101:8
-
Journal article (peer-reviewed)abstract
- Recent studies have established that the immune system plays an important role in the development of atherosclerosis. However, its role in regulating the arterial response to mechanical injury is less well studied. Arterial injury is associated with local accumulation of antibodies, and mice lacking functional T and B cells exhibit increased neointima formation, indicating that adaptive immune responses to neoantigens in the damaged tissue modulate the vascular repair process. To study the role of lipid antigen presentation in the arterial response to injury, we analyzed neointima formation in mice deficient in the lipid antigen-presenting molecule CD1d using a carotid collar model. As compared with control mice, neointima formation was reduced by >60% (P<0.01) in CD1d-/- mice. Moreover, carotid injury of wild-type C57BL/6 mice was associated with expansion of CD1d-restricted natural killer T cells in the spleen and accumulation of natural killer T cells in the periadventitial space of injured arteries. The results suggest that presentation of lipid antigens through the CD1d-natural killer T cell pathway modulates vascular repair responses.
|
|
| 31. |
- Svenugnsson, Elisabet, et al.
(author)
-
Decreased levels of autoantibodies against apolipoprotein B-100 antigens are associated with cardiovascular disease in systemic lupus erythematosus.
- 2015
-
In: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 181:3, s. 417-426
-
Journal article (peer-reviewed)abstract
- Increased production of autoantibodies is a characteristic feature of systemic lupus erythematosus (SLE) and there is evidence that several of these autoantibodies may contribute to the increased cardiovascular disease (CVD) in SLE. Autoantibodies against the apolipoprotein (apo) B-100 peptides p45 and p210 have been associated with a lower CVD risk in non-SLE cohorts. The aim of the present study was to investigate how SLE affects the occurrence of these potentially protective autoantibodies. The study cohort consisted of 434 SLE patients and 322 age and sex-matched population controls. Antibodies against native and malondialdehyde (MDA)-modified p45 and p210 were measured by ELISA. SLE patients had significantly lower levels of p210 IgG and p45 IgM (both the native and MDA-modified forms). SLE patients with manifest CVD (myocardial infarction, ischemic cerebrovascular disease or peripheral vascular disease) had lower levels p210 IgG and p45 IgM than SLE patients without CVD. Decreased levels of these autoantibodies were also observed in SLE patients with permanent organ damage as assessed by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index (SDI). The present findings show that patients with SLE, a condition generally characterized by abundance of autoantibodies of multiple specificities, have reduced levels of antibodies against the apo B-100 antigens p45 and p210 and that the levels of these antibodies are further reduced in SLE patients with CVD. These observations suggest the possibility that an impaired antibody-mediated removal of damaged LDL particles may contribute to the development of vascular complications and organ damage in SLE. This article is protected by copyright. All rights reserved.
|
|
| 32. |
- Tano, Ingrid, 1968-, et al.
(author)
-
Relationships between Coating Microstructure and Thermal Conductivity in Thermal Barrier Coatings – A modelling Approach
- 2010
-
In: International Thermal Spray Conference and Exposition, ITCS Singapore 2010. - Düsseldorft : DVS Media. - 9783871555909 ; , s. 66-72
-
Conference paper (peer-reviewed)abstract
- Fundamental understanding of relationships between coating microstructure and thermal conductivity is important to be able to understand the influence of coating defects, such as delaminations and pores, on heat insulation in thermal barrier coatings. Object-Oriented Finite element analysis (OOF) has recently been shown as an effective tool for evaluating thermo-mechanical material behaviour, because of this method's capability to incorporate the inherent material microstructure as an input to the model. In this work, this method was combined with multi-variate statistical modelling. The statistical model was used for screening and tentative relationship building and the finite element model was thereafter used for verification of the statistical modelling results. Characterisation of the coatings included microstructure, porosity and crack content and thermal conductivity measurements. A range of coating architectures was investigated including High purity Yttria stabilised Zirconia, Dysprosia stabilised Zirconia and Dysprosia stabilised Zirconia with porosity former. Evaluation of the thermal conductivity was conducted using the Laser Flash Technique. The microstructures were examined both on as-sprayed samples as well as on heat treated samples. The feasibility of the combined two modelling approaches, including their capability to establish relationships between coating microstructure and thermal conductivity, is discussed.
|
|
| 33. |
|
|
| 34. |
- Wigren, Maria, et al.
(author)
-
Atheroprotective effects of Alum are associated with capture of oxidized LDL antigens and activation of regulatory T cells
- 2009
-
In: Circulation Research. - 0009-7330 .- 1524-4571. ; 104:12, s. e62-70
-
Journal article (peer-reviewed)abstract
- The immune system represents a promising novel target for prevention of atherosclerosis. Several pilot vaccines that reduce atherosclerosis in experimental animals have been developed. The aluminum hydroxide adjuvant Alum has been shown to have antiatherogenic properties in itself, suggesting that it may be a suitable adjuvant in possible future atherosclerosis vaccines. To characterize the immune pathways mediating this protection, we treated wild-type C57BL/6 and Apoe(-)(/)(-) mice with Alum or PBS. Analyses of splenocytes isolated from 12-week-old mice demonstrated that Alum increased the presence of CD4(+)CD25(+)FoxP3(+) regulatory T cells and downregulated the expression of T cell activation markers CD28 and ICOS in Apoe(-)(/)(-) mice but not in C57BL/6 wild-type mice. A similar immunosuppressive phenotype was found also in 25-week-old Apoe(-)(/)(-) mice and was associated with reduced atherosclerosis. Alum precipitates recovered from the injection site of Apoe(-)(/)(-) mice contained antigens derived from oxidized LDL. These findings demonstrate that treatment of Apoe(-)(/)(-) mice with Alum results in an increase of regulatory T cells and suggest that these are activated by tolerogenic antigen-presenting cells presenting oxidized LDL antigens. Our findings provide improved mechanistic understanding of the atheroprotective properties of aluminum hydroxide adjuvants but also point to the importance of determining if hypercholesterolemia may compromise the efficacy of Alum-containing vaccines used clinically today.
|
|
| 35. |
- Wigren, Maria, et al.
(author)
-
Cardiovascular disease in systemic lupus erythematosus is associated with increased levels of biomarkers reflecting receptor-activated apoptosis
- 2018
-
In: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 270, s. 1-7
-
Journal article (peer-reviewed)abstract
- Background and aims: There is convincing evidence that adaptive immune responses affect the development of atherosclerosis and thrombosis and several autoimmune diseases are associated with increased cardiovascular risk. However, our understanding of the underlying mechanisms remains limited. We investigated how biomarkers reflecting four aspects of autoimmunity: apoptosis, inflammation, tissue degradation and repair, associate with cardiovascular disease (CVD) in subjects with systemic lupus erythematosus (SLE). Methods: We investigated 484 well-characterized SLE patients, 69 of whom had CVD (coronary artery disease, cerebrovascular disease or peripheral artery disease), and 253 controls. Occurrence of carotid plaques was investigated with ultrasound. Plasma levels of biomarkers reflecting apoptosis (Fas, TNF receptor 1, TRAIL receptor 2), inflammation (IL-6, IL-8, monocyte chemotactic protein-1), tissue degradation (matrix metalloproteinase (MMP)-1, MMP-3, MMP-7), and tissue repair (platelet-derived growth factor, epidermal growth factor and stem cell factor) were analyzed by Proximity Extension Assay. Results: Subjects with SLE had markedly elevated plasma levels of biomarkers reflecting apoptosis, inflammation and tissue degradation as compared to controls. SLE patients with CVD had higher levels of Fas, TNF receptor 1, TRAIL receptor 2, MMP-1 and -7 than those without CVD. The same associations were found for the presence of a carotid plaque. When controlling for the factors included in the Framingham risk score, all biomarkers except MMP-1 remained associated with the presence of a carotid plaque, while only TRAIL receptor 2 levels remained significantly associated with CVD. Conclusions: Our findings argue that the cardiovascular risk in SLE is associated with increased cell death by apoptosis and tissue degradation.
|
|
| 36. |
- Wigren, Maria, et al.
(author)
-
Decreased levels of stem cell factor in subjects with incident coronary events
- 2016
-
In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 279:2, s. 180-191
-
Journal article (peer-reviewed)abstract
- BACKGROUND: It has been proposed that vascular progenitor cells play an important role in vascular repair, but their possible clinical importance in cardiovascular disease has not been fully characterized. Vascular endothelial growth factor A, placental growth factor and stem cell factor (SCF) are three growth factors that are important in recruiting vascular progenitor cells. In this study, we investigated the association between the plasma levels of these growth factors and incident coronary events (CEs).METHODS: Levels of the three growth factors were measured using the proximity extension assay technique in baseline plasma samples from 384 subjects with a first CE (mean follow-up 14.0 ± 4.3 years) and 409 event-free control subjects matched by sex and age, as well as in homogenates from 201 endarterectomy specimens.RESULTS: After controlling for known cardiovascular disease risk factors in a Cox regression model, subjects in the lowest SCF tertile had a hazard ratio of 1.70 (95% confidence interval 1.14-2.54) compared with subjects in the highest SCF tertile. Lower SCF levels were also associated with more severe carotid disease, less fibrous atherosclerotic plaques and an increased incidence of heart failure. Expression of the SCF receptor c-kit was demonstrated in the subendothelial layer and fibrous cap of human atherosclerotic plaques. Smokers and subjects with diabetes had decreased levels of SCF compared with control subjects.CONCLUSION: To our knowledge, this is the first clinical study to provide evidence to support a key role for SCF and progenitor cells in vascular repair. We suggest that the SCF-c-kit pathway may be a promising biomarker and therapeutic target in cardiovascular disease.
|
|
| 37. |
- Wigren, Maria, et al.
(author)
-
Evidence for a role of regulatory T cells in mediating the atheroprotective effect of apolipoprotein B peptide vaccine.
- 2011
-
In: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 269, s. 546-556
-
Journal article (peer-reviewed)abstract
- Abstract. Wigren M, Kolbus D, Dunér P, Ljungcrantz I, Söderberg I, Björkbacka H, Fredrikson GN, Nilsson J. (Malmö University Hospital, Lund University; Malmö University, Malmo; Sweden) Evidence for a role of regulatory T cells in mediating the atheroprotective effect of apolipoprotein B peptide vaccine. J Intern Med 2010; doi: 10.1111/j.13 65-2796.2010.02311.x. Objectives. Autoimmune responses against oxidized low-density lipoprotein are considered to play an important pro-inflammatory role in atherosclerosis and to promote disease progression. T-regulatory cells (Tregs) are immunosuppressive cells that have an important part in maintaining self-tolerance and protection against autoimmunity. We investigated whether aBp210, a prototype atherosclerosis vaccine based on a peptide sequence derived from apolipoprotein B, inhibits atherosclerosis through the activation of Tregs. Design. Six-week-old Apoe(-/-) mice were immunized with aBp210 and received booster immunizations 3 and 5 weeks later, as well as 1 week before being killed at 25 weeks of age. Results. At 12 weeks, immunized mice had increased expression of the Treg marker CD25 on circulating CD4 cells, and concanavalin A (Con A)-induced interferon-γ, interleukin (IL)-4, and IL-10 release from splenocytes was markedly depressed. At 25 weeks, there was a fivefold expansion of splenic CD4+ CD25+ Foxp3 Tregs, a 65% decrease in Con A-induced splenic T-cell proliferation and a 37% reduction in the development of atherosclerosis in immunized mice. Administration of blocking antibodies against CD25 neutralized aBp210-induced Treg activation as well as the reduction of atherosclerosis. Conclusions. The present findings demonstrate that immunization of Apoe(-/-) mice with the apolipoprotein B peptide vaccine aBp210 is associated with activation of Tregs. Administration of antibodies against CD25 results in depletion of Tregs and blocking of the atheroprotective effect of the vaccine. Modulation in atherosclerosis-related autoimmunity by antigen-specific activation of Tregs represents a novel approach for treatment of atherosclerosis.
|
|
| 38. |
|
|
| 39. |
- Wigren, Maria, et al.
(author)
-
Lack of Ability to Present Antigens on Major Histocompatibility Complex Class II Molecules Aggravates Atherosclerosis in ApoE-/- Mice
- 2019
-
In: Circulation. - 1524-4539. ; 139:22, s. 2554-2566
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Hypercholesterolemic mice lacking factors required for activation of CD4+ T cells are characterized by reduced development of atherosclerosis. Consequently, it has been assumed that atherosclerosis involves loss of tolerance against modified self-antigens generated in response to hypercholesterolemia and that presentation of such antigens on major histocompatibility complex class II (MHCII) leads to activation of proatherogenic Th1 cells. In this study, we wanted to determine the role of antigen presentation on MHCII in atherosclerosis development.METHODS: Apolipoprotein E (ApoE-/-) mice deficient for MHCII (ApoE-/-MHCII-/-) were used to study the role of MHCII in atherosclerosis development.RESULTS: Compared with ApoE-/- mice, ApoE-/-MHCII-/- mice had reduced levels of CD4+ T cells, immunoglobulin G and M levels, and Th1 and Th2 cytokines in plasma. CD8+ T cells were increased and regulatory T cells were reduced both in spleen and in lesions of ApoE-/-MHCII-/- mice. Decreased plasma levels of inflammatory cytokines in ApoE-/-MHCII-/- mice indicated reduced systemic inflammation. Despite this, ApoE-/-MHCII-/- mice had significantly more atherosclerosis as assessed by en face Oil Red O staining of the aorta (4.7±2.9% versus 1.9±1.3%; P<0.01) and cross-sectional area of subvalvular lesions (7.7±2.2×105 µm2 versus 4.6±2.8×105 µm2; P<0.05). Cell transfer and blocking antibody studies suggested that loss of regulatory T cells is the most important cause of aggravated atherosclerosis in ApoE-/-MHCII-/- mice.CONCLUSIONS: Our observations demonstrate that antigen presentation on MHCII has important protective functions in atherosclerosis and that this is primarily the result of activation of regulatory T cells. These findings have implications for understanding the possible risks and benefits of immunosuppressive therapy in patients with cardiovascular disease.
|
|
| 40. |
- Wigren, Maria, et al.
(author)
-
Low Levels of Circulating CD4+FoxP3+ T Cells Are Associated With an Increased Risk for Development of Myocardial Infarction But Not for Stroke.
- 2012
-
In: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1524-4636 .- 1079-5642. ; 32:8, s. 2000-2007
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: Regulatory T cells (Tregs) protect against atherosclerosis in experimental models, but their association with cardiovascular disease in humans remains to be elucidated. The aim of the present study was to determine whether circulating Tregs predict the development of acute cardiovascular events in humans. METHODS AND RESULTS: The study cohort consisted of a random sample of participants (n=700), aged 68 to 73 years, from the Malmo Diet and Cancer Study. Mononuclear leukocytes, stored at -140°C at the baseline investigation in 1991.1994, were thawed and Tregs, defined by the expression of FoxP3 in CD4+ T cells, were analyzed by flow cytometry. There was no detectable loss of cells during storage, and the viability of thawed leukocytes was 95%. A low fraction of both CD4+FoxP3+ and CD4+CD25+FoxP3+ T cells was associated with a higher release of proinflammatory cytokines from activated mononuclear leukocytes, and this association was strongest for CD4+FoxP3+ cells. Eighty-four coronary events and 66 strokes were registered during follow-up until December 31, 2008. In a Cox proportional hazard regression model adjusting for major risk factors, low levels of baseline CD4+FoxP3+ T cells were associated with an increased risk for the development of acute coronary events but not stroke. There were no associations between CD4+CD25+FoxP3+ T cells and development of an acute coronary event or stroke. CONCLUSIONS: This study provides prospective evidence for the role of Tregs in the development of myocardial infarction. The findings are in accordance with previous experimental studies and provide clinical support for a protective role of Tregs in atherosclerosis. The lack of association between Tregs and stroke may reflect the more heterogeneous cause of this disease.
|
|
| 41. |
- Wigren, Maria, et al.
(author)
-
Lymphocytes in atherosclerosis
- 2012
-
In: Clinica Chimica Acta. - : Elsevier BV. - 0009-8981. ; 413:19-20, s. 1562-1568
-
Research review (peer-reviewed)abstract
- It is well established that atherosclerosis is caused by an inflammatory process in the arterial intima. However, it is only in recent years that it has become clear that this inflammation is modulated by immune responses against plaque antigens. These antigens are primarily believed to be modified self-antigens such as oxidized LDL. The immune system is challenged to determine whether these antigens should be regarded self and tolerated or non-self and eliminated. The latter will result in plaque development while the first will be protective. T cells are key effectors of both types of responses. An activation of regulatory T cells inhibits auto-reactive T effector cells and is anti-inflammatory. In contrast, if Th1 cells become activated in the plaque this is associated with increased inflammation and disease progression. The role of B cells in atherosclerosis remains to be clarified but some species of athero-protective antibodies have been identified. The elucidation of role of immune system in atherosclerosis has revealed new targets for intervention and both vaccines and antibody-based therapies are presently in or due to enter clinical testing. (c) 2012 Elsevier B.V. All rights reserved.
|
|
| 42. |
- Wigren, Maria, et al.
(author)
-
Pathogenic immunity in systemic lupus erythematous and atherosclerosis: common mechanisms and possible targets for intervention.
- 2015
-
In: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 278:5, s. 494-506
-
Research review (peer-reviewed)abstract
- Systemic lupus erythematous (SLE) is an autoimmune disorder that primarily affects young women and is characterized by inflammation in several organs including the kidneys, skin, joints, blood, and nervous system. Abnormal immune cellular and humoral responses play important roles in the development of the disease process. Impaired clearance of apoptotic material is a key factor contributing to activation of self-reactive immune cells. The incidence of atherosclerotic cardiovascular disease (CVD) is increased up to 50-fold in SLE patients compared to age- and gender-matched control subjects and this can only partly be explained by traditional risk factors for CVD. Currently, there is no effective treatment to prevent CVD complications in SLE. Traditional preventive CVD therapies have not been found to significantly lower the incidence of CVD in SLE; therefore, there is a need for novel treatment strategies and increased understanding of the mechanisms involved in the pathogenesis of CVD complications in SLE. The pathogenic immune responses in SLE and development of atherosclerotic plaques share some characteristics, such as impaired efferocytosis and skewed T cell activation, suggesting the possibility of identifying novel targets for intervention. As novel immune-based therapies for CVD are being developed, it is possible that some of these may be effective for the prevention of CVD and for immunomodulation in SLE. However, further understanding of the mechanisms leading to an increased prevalence of cardiovascular events in SLE is critical for the development of such therapies. This article is protected by copyright. All rights reserved.
|
|
| 43. |
|
|
| 44. |
- Xue, Ling, et al.
(author)
-
FADD, Caspase-3, and Caspase-8 and Incidence of Coronary Events
- 2017
-
In: Arteriosclerosis, Thrombosis, and Vascular Biology. - 1524-4636. ; 37:5, s. 983-989
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: To investigate the relationship between 3 markers of apoptosis, that is, FADD (Fas-associated death domain-containing protein), caspase-3, and caspase-8, and incidence of coronary events (CEs) in a population-based cohort study.APPROACH AND RESULTS: In vitro experiments were performed to assess the response of the apoptotic biomarkers after Fas stimulation of peripheral blood mononuclear cells. The experiments showed significantly increased releases of FADD, caspase-3, and caspase-8 after Fas stimulation. The relationship between FADD, caspase-3, and caspase-8, respectively, and incidence of CEs was studied in 4284 subjects from the population-based Malmö Diet and Cancer Study. Cox' proportional hazards regression was used to examine the association between the apoptotic biomarkers and incidence of CE over a mean follow-up of 19 years. A total of 381 individuals had CE during the follow-up. High FADD at baseline was significantly associated with incident CE. In the highest compared with the lowest quartile of FADD, the risk factor adjusted hazards ratio for CE was 1.82 (95% confidence interval, 1.35-2.46; P for trend <0.001). A significant association was also found between caspase-8 and CE; the hazards ratio (Q4 versus Q1) was 1.90 (95% confidence interval, 1.39-2.60; P for trend <0.001) after adjustment for risk factors. No association was found between caspase-3 and CEs.CONCLUSIONS: High levels of FADD and caspase-8, but not caspase-3, were associated with increased incidence of CE in subjects from the general population. The in vitro experiments support the view that these biomarkers could reflect activation of the extrinsic apoptotic pathway.
|
|
| 45. |
- Yao Mattisson, Ingrid, et al.
(author)
-
Elevated Markers of Death Receptor-Activated Apoptosis are Associated with Increased Risk for Development of Diabetes and Cardiovascular Disease
- 2017
-
In: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 26, s. 187-197
-
Journal article (peer-reviewed)abstract
- Background An increased rate of cell death by apoptosis has been implicated in both diabetes and atherosclerosis. Apoptosis can be induced through activation of the death receptors TNF receptor 1 (TNFR-1), TRAIL receptor 2 (TRAILR-2) and Fas. Soluble forms of these receptors are found in plasma. The objective of this study was to determine if soluble death receptors are markers of receptor-activated apoptosis and predict risk for development of diabetes and cardiovascular events. Methods Fas ligand was used to induce apoptosis in peripheral blood mononuclear cells and INS-1 pancreatic β-cells and release of TNFR-1, TRAILR-2 and Fas measured by ELISA. Proximity Extension Assay was used to analyze plasma levels of TNFR-1, TRAILR-2 and Fas in baseline samples of 4742 subjects in the Malmö Diet and Cancer Study and related to development of diabetes and cardiovascular events during 19.2 years of follow-up. Results Activation of apoptosis by Fas ligand was associated with release of soluble Fas, TNFR-1 and TRAILR-2 in both cell types. Circulating levels of all three receptors were higher in subjects with diabetes and correlated with markers of impaired glucose metabolism in non-diabetic subjects. Among the latter, those in the highest tertile of soluble Fas, TNFR-1 and TRAILR-2 had increased risk for development of diabetes and cardiovascular events. These associations became weaker when adjusting for cardiovascular risk factors in Cox regression models, but remained significant for TRAILR-2 with incident diabetes, cardiovascular mortality, myocardial infarction and ischemic stroke, and for TNFR-1 with myocardial infarction. Conclusion The present study demonstrates an association between several cardiovascular risk factors and elevated levels of circulating markers of apoptotic cell death. It also shows that subjects with high levels of these biomarkers have increased risk of diabetes and CVD. This implies that soluble death receptors are markers of β-cell and vascular injury and potentially could be used as surrogate markers of therapeutic efficiency in risk factor interventions.
|
|
| 46. |
- Zetterqvist, Anna, et al.
(author)
-
Inhibition of nuclear factor of activated T-cells (NFAT) suppresses accelerated atherosclerosis in diabetic mice.
- 2013
-
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:6
-
Journal article (peer-reviewed)abstract
- Diabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis.
|
|
| 47. |
- Zhao, Ming, et al.
(author)
-
Fc{gamma}RIIB Inhibits the Development of Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice.
- 2010
-
In: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 184:5, s. 2253-2260
-
Journal article (peer-reviewed)abstract
- The immune processes associated with atherogenesis have received considerable attention during recent years. IgG FcRs (FcgammaR) are involved in activating the immune system and in maintaining peripheral tolerance. However, the role of the inhibitory IgG receptor FcgammaRIIB in atherosclerosis has not been defined. Bone marrow cells from FcgammaRIIB-deficient mice and C57BL/6 control mice were transplanted to low-density lipoprotein receptor-deficient mice. Atherosclerosis was induced by feeding the recipient mice a high-fat diet for 8 wk and evaluated using Oil Red O staining of the descending aorta at sacrifice. The molecular mechanisms triggering atherosclerosis was studied by examining splenic B and T cells, as well as Th1 and Th2 immune responses using flow cytometry and ELISA. The atherosclerotic lesion area in the descending aorta was approximately 5-fold larger in mice lacking FcgammaRIIB than in control mice (2.75 +/- 2.57 versus 0.44 +/- 0.42%; p < 0.01). Moreover, the FcgammaRIIB deficiency resulted in an amplified splenocyte proliferative response to Con A stimulation (proliferation index 30.26 +/- 8.81 versus 2.96 +/- 0.81%, p < 0.0001) and an enhanced expression of MHC class II on the B cells (6.65 +/- 0.64 versus 2.33 +/- 0.25%; p < 0.001). In accordance, an enlarged amount of CD25-positive CD4 T cells was found in the spleen (42.74 +/- 4.05 versus 2.45 +/- 0.31%; p < 0.0001). The plasma Ab and cytokine pattern suggested increased Th1 and Th2 immune responses, respectively. These results show that FcgammaRIIB inhibits the development of atherosclerosis in mice. In addition, they indicate that absence of the inhibiting IgG receptor cause disease, depending on an imbalance of activating and inhibiting immune cells.
|
|
| 48. |
- Zoric, Neven, et al.
(author)
-
Quantitative PCR: A promising technique investigating the early bone-implant interface
- 2007
-
In: Abstract, European Association for Osseointegration (EAO), 16th Annual Scientific Meeting, Barcelona, Spain. ; 25-27 October
-
Conference paper (peer-reviewed)abstract
- Objectives: Studies on the early tissue response to materials are difficult due to the inaccessibility of the interface zone and lack of sensitive techniques. The purpose of the present study was to apply quantitative PCR (qPCR) in combination with LM and SEM for the evaluation of early gene expression response as well as cellular reactions close to titanium implants. Experimental methods: Anodically oxidized titanium (TiUniteTM; Nobel Biocare AB) and machined titanium implants (2mm×2mm) were inserted in the rat tibia. After 1,3, and 6 days, implants were unscrewed and surrounding bone was retrieved. Both the implants and bone were analyzed with qPCR, routine histology and SEM. The amount of mRNA was normalized to 18S protein subunit. Results: After the initial inflammatory response, the tissue located inside the threads became rapidly organized. SEM analysis showed mesenchymal-like cells extending their processes into the pores of the anodically oxidized surface. qPCR demonstrated significantly higher 18S around anodically oxidized screws and in the surrounding tissues. Alkaline phosphatase (osteoblast marker), TRAP and Cathepsin K (osteoclast markers) mRNA, but not the inflammatory markers (TNF-alpha and IL-1beta) were expressed at different levels around the two surfaces. Conclusions: The results demonstrate that the experimental model and qPCR provide interesting possibilities to analyze the mechanisms of osseointegration. Furthermore, remodelling and in particular the molecular processes occur at implant surfaces in vivo already 3 days after implantation. Support: Swedish Research Council and the Institute for Biomaterials and Cell Therapy, Göteborg, Sweden
|
|
