| 1. |
- Berglund, Lisa, et al.
(författare)
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Nuclear Factor of Activated T Cells Regulates Osteopontin Expression in Arterial Smooth Muscle in Response to Diabetes-Induced Hyperglycemia
- 2010
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Ingår i: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY. - Baltimore : Lippincott Williams & Wilkins. - 1079-5642. ; 30, s. 154-218
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Tidskriftsartikel (refereegranskat)abstract
- Objective-Hyperglycemia is a recognized risk factor for cardiovascular disease in diabetes. Recently, we reported that high glucose activates the Ca2+/calcineurin-dependent transcription factor nuclear factor of activated T cells (NFAT) in arteries ex vivo. Here, we sought to determine whether hyperglycemia activates NFAT in vivo and whether this leads to vascular complications. Methods and Results-An intraperitoneal glucose-tolerance test in mice increased NFATc3 nuclear accumulation in vascular smooth muscle. Streptozotocin-induced diabetes resulted in increased NFATc3 transcriptional activity in arteries of NFAT-luciferase transgenic mice. Two NFAT-responsive sequences in the osteopontin (OPN) promoter were identified. This proinflammatory cytokine has been shown to exacerbate atherosclerosis and restenosis. Activation of NFAT resulted in increased OPN mRNA and protein in native arteries. Glucose-induced OPN expression was prevented by the ectonucleotidase apyrase, suggesting a mechanism involving the release of extracellular nucleotides. The calcineurin inhibitor cyclosporin A or the novel NFAT blocker A-285222 prevented glucose-induced OPN expression. Furthermore, diabetes resulted in higher OPN expression, which was significantly decreased by in vivo treatment with A-285222 for 4 weeks or prevented in arteries from NFATc3(-/-) mice. Conclusions-These results identify a glucose-sensitive transcription pathway in vivo, revealing a novel molecular mechanism that may underlie vascular complications of diabetes.
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| 2. |
- Björkbacka, Harry, et al.
(författare)
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Low Levels of Apolipoprotein B-100 Autoantibodies Are Associated With Increased Risk of Coronary Events.
- 2016
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 36, s. 765-771
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Previous smaller studies have indicated inverse associations between autoantibodies to oxidized low-density lipoprotein epitopes, and cardiovascular disease. The present study investigated associations between autoantibodies against the apolipoprotein B-100 peptides p45 and p210, respectively, and risk of incident cardiovascular disease in a large population-based cohort. APPROACH AND RESULTS: Apolipoprotein B-100 autoantibodies were analyzed by ELISA in a prospective study, including 5393 individuals (aged 46-68 years) belonging to the cardiovascular arm of the Malmö Diet and Cancer study with a follow-up time of >15 years. Subjects that suffered an acute coronary event during follow-up (n=382) had lower levels at baseline of IgM autoantibodies recognizing the native and malondialdehyde-modified apolipoprotein B-100 peptides p45 and p210 and also lower IgG levels recognizing native p210, whereas no association was found with risk for stroke (n=317). Subjects in the highest compared with lowest tertile of IgM-p45MDA (hazard ratio [95% confidence interval]: 0.72 [0.55, 0.94]; P=0.017) and IgG-p210native (hazard ratio [95% confidence interval]: 0.73 [0.56, 0.97]; P=0.029) had lower risk for incident coronary events after adjustment for cardiovascular risk factors in Cox proportional hazard regression models. Moreover, subjects with high levels of IgG-p210native were less likely to have carotid plaques as assessed by ultrasonography at baseline (odds ratio=0.81, 95% confidence interval 0.70-0.95, P=0.008 after adjustment for risk factors). CONCLUSIONS: This large prospective study demonstrates that subjects with high levels of apolipoprotein B-100 autoantibodies have a lower risk of coronary events supporting a protective role of these autoantibodies in cardiovascular disease.
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| 3. |
- Dimayuga, Paul C, et al.
(författare)
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T Cell Modulation of Intimal Thickening After Vascular Injury. The Bimodal Role of IFN-{gamma} in Immune Deficiency.
- 2005
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 25:Oct 13, s. 2528-2534
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Tidskriftsartikel (refereegranskat)abstract
- Background - Immune deficiency results in exuberant intimal thickening after arterial injury. The mechanisms involved are not well defined. We investigated the role of T cells and IFN-gamma in the response to injury in normal and immune-deficient Rag-1KO mice. Methods and Results - Carotid arterial injury was induced in wild-type (WT), Rag-1KO mice, and Rag-1KO mice reconstituted with T cell-enriched splenocytes. The exuberant intimal thickening in Rag-1KO mice compared with WT mice 21 days after injury was reduced by T cell transfer (P < 0.01). Exogenous IFN-gamma starting on the day of injury inhibited intimal thickening in Rag-1KO mice. However, antibody neutralization of endogenous IFN-gamma in Rag-1KO mice starting 7 days after injury decreased intimal thickening, indicating that late presence of IFN-gamma promoted intimal thickening in Rag-1KO mice. Results further suggest that the effect of late IFN-gamma in Rag-1KO mice is mediated in part by increased IRF-1 and iNOS expression, coupled with low SOCS1 expression. Conclusion - T cells inhibit intimal thickening in the early stages of the response to injury through basal IFN-gamma secretion. In the Rag-1KO mice, late IFN-gamma expression promotes intimal thickening. These findings add novel insight to conditions of immune deficiency that affect intimal thickening.
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| 4. |
- Dimayuga, Paul, et al.
(författare)
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Inhibitory effect on arterial injury-induced neointimal formation by adoptive B-cell transfer in Rag-1 knockout mice.
- 2002
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1524-4636 .- 1079-5642. ; 22:4, s. 644-649
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the effect of B-cell reconstitution in immune-deficient Rag-1 knockout (KO) mice subjected to arterial injury. After 21 days, injury induced a 4- to 5-fold increase in neointimal formation in Rag-1 KO mice fed normal chow compared with wild-type (WT) mice (0.020+/-0.0160 [n=8] versus 0.0049+/-0.0022 [n=8] mm(2), respectively; P<0.05) and in western-type diet-fed Rag-1 KO mice compared with WT mice (0.0312+/-0.0174 [n=7] versus 0.0050+/-0.0028 [n=6] mm(2), respectively; P<0.05). To investigate the role of B cells in response to injury, Rag-1 KO mice were reconstituted with B cells derived from the spleens of WT mice, with donors and recipients on the same diet. Reconstitution of Rag-1 KO mice with B cells from WT mice (both fed normal chow) reduced neointimal formation compared with the effect in unreconstituted Rag-1 KO mice (0.0076+/-0.0039 [n=9] versus 0.020+/-0.0160 [n=8] mm(2), respectively; P<0.05). Reconstitution of Rag-1 KO mice with B cells from WT mice (both fed a western diet) reduced neointimal formation compared the effect in Rag-1 KO mice (0.0087+/-0.0037 [n=8] versus 0.0312+/-0.0174 [n=7] mm(2), respectively; P<0.05). Injured carotid arteries from reconstituted Rag-1 KO mice had detectable IgM and IgG, indicating viable transfer of B cells. The results suggest that B cells modulate the response to arterial injury.
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| 5. |
- Goncalves, Isabel, et al.
(författare)
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Elevated Plasma Levels of MMP-12 Are Associated With Atherosclerotic Burden and Symptomatic Cardiovascular Disease in Subjects With Type 2 Diabetes.
- 2015
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 35:7, s. 1723-1731
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Tidskriftsartikel (refereegranskat)abstract
- Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus.
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| 6. |
- Goncalves, Isabel, et al.
(författare)
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Humoral Immune Response Against Defined Oxidized Low-Density Lipoprotein Antigens Reflects Structure and Disease Activity of Carotid Plaques.
- 2005
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 25:6, s. 1250-1255
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Tidskriftsartikel (refereegranskat)abstract
- Background - Immune responses against oxidized low- density lipoprotein ( LDL) play an important role in atherosclerosis. The aim of this study was to investigate if humoral immune response against specific oxidized LDL antigens, such as aldehyde- modified peptide sequences of apolipoprotein B- 100, reflects disease activity and structure of atherosclerotic plaques. Methods and Results - Plaques were obtained from 114 symptomatic subjects referred to carotid endarterectomy and characterized immunohistochemically and histologically. Plasma levels of IgG and IgM against aldehyde- modified apolipoprotein B- 100 amino acid sequences 661 to 680, 3136 to 3155 ( peptide 210), and 3661 to 3680 ( peptide 240) were determined by enzyme- linked immunosorbent assay. High levels of IgG against peptide 210 were associated with increased plaque content of lipids ( r = 0.24, P < 0.05) and hemorrhage ( r = 0.27, P = 0.005), with decreased content of fibrous tissue ( r = - 0.25, P = 0.01), but also with lower total plaque volume ( r = - 0.21, P < 0.05). In contrast, high levels of IgM against peptide 240 were associated with plaques with more fibrous tissue ( r = 0.35, P < 0.001), less lipids ( r = - 0.34, P < 0.001), and less macrophages ( r = - 0.24, P < 0.05). IgM against peptide 210 were found to be associated with plaque fibrous tissue ( r = 0.20, P < 0.05), less lipids ( r = - 0.21, P < 0.05), and less macrophages ( r = - 0.27, P = 0.01). Conclusion - These findings support the notion that immune responses against oxidized LDL epitopes are involved in atherosclerosis and that the level of circulating antibodies against these structures may reflect disease activity in the arterial wall.
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| 7. |
- Herbin, Olivier, et al.
(författare)
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Regulatory T-Cell Response to Apolipoprotein B100-Derived Peptides Reduces the Development and Progression of Atherosclerosis in Mice
- 2012
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 32:3, s. 144-605
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Tidskriftsartikel (refereegranskat)abstract
- Objective-The immunoinflammatory response plays a critical role in the development and progression of atherosclerosis. Recent studies suggested an important role for regulatory T (Treg) cells in the inhibition of disease-related vascular inflammation. We hypothesized that induction of a specific Treg cell response to atherosclerosis-relevant antigens would be an attractive strategy to limit the development and progression of atherosclerosis through the promotion of immune tolerance. Methods and Results-Young or old Apoe(-/-) mice were subcutaneously infused for 2 weeks with either a control ovalbumin (OVA) peptide or with apolipoprotein B100 (ApoB100)-derived peptides without adjuvant. Atherosclerosis development, progression and immunologic status were assessed at 8 weeks after the end of the infusion. Treatment with ApoB100 peptides led to significant reduction of lesion development in young Apoe(-/-) mice (P=0.001 versus OVA group) and abrogated atherosclerosis progression in old Apoe(-/-) mice with already established lesions (0% progression in ApoB100 versus 17% in OVA group, P<0.005). Limitation of plaque progression was associated with reduced vascular inflammation and increased collagen content, indicative of plaque stabilization. Infusion of ApoB100 peptides did not alter antibody production but promoted a specific Treg cell response, which was associated with a reduction of both T helper type 1-related and T helper type 2-related cytokines. Interestingly, depletion of CD4(+)CD25(+) Treg cells abrogated ApoB100 peptides-dependent immune modulation and atheroprotection. Conclusion-Subcutaneous infusion of adjuvant-free ApoB100-derived peptides to Apoe(-/-) mice reduces atherosclerosis through the induction of a specific Treg cell response. (Arterioscler Thromb Vasc Biol. 2012;32:605-612.)
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| 8. |
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| 9. |
- Mantani, Polyxeni, et al.
(författare)
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Circulating CD40(+) and CD86(+) B Cell Subsets Demonstrate Opposing Associations With Risk of Stroke
- 2014
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1079-5642 .- 1524-4636. ; 34:1, s. 211-218
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Tidskriftsartikel (refereegranskat)abstract
- Objective-Accumulating evidence shows that immune cells play an important role in atherosclerosis. Most attention has focused on the role of different T cell subsets, whereas the possible involvement of B cells has been less studied. In this study, we assessed the association of 2 different B cell subsets, CD19(+)CD40(+) and CD19(+)CD86(+) B cells, with risk for development of acute cardiovascular events. Approach and Results-The prospective study included 700 subjects randomly selected from the cardiovascular cohort of the Malmo Diet and Cancer study. Mononuclear leukocytes, stored at -140 degrees C at the baseline investigation in 1991-1994, were thawed and B cell subsets analyzed by flow cytometry. Cytokine release from CD3/CD28-stimulated mononuclear leukocytes was measured with multiplex ELISA. Baseline carotid intima-media thickness and stenosis were assessed by ultrasonography, and clinical events were monitored through validated national registers during a median/mean follow-up time of 15 years. The subjects in the highest tertile of CD19(+)CD40(+) B cells had a significantly lower risk of incident stroke after adjustment for other risk factors. In contrast, CD19(+)CD86(+) B cells were associated with higher risk for development of a stroke event and increased release of proinflammatory cytokines from mononuclear leukocytes. Conclusions-These observations provide evidence for an involvement of B cells in the incidence of stroke and suggest that both pathogenic and protective B cell subsets exist.
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| 10. |
- Nordin Fredrikson, Gunilla, et al.
(författare)
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Identification of Immune Responses Against Aldehyde-Modified Peptide Sequences in ApoB Associated With Cardiovascular Disease.
- 2003
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : The Assoc.. - 1524-4636 .- 1079-5642. ; 23:5, s. 872-878
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Tidskriftsartikel (refereegranskat)abstract
- Objective— Atherosclerosis is associated with an immune response against oxidized LDL, which modulates the progression of the disease process. Methods and Results— Using a library of polypeptides covering the complete sequence of apoB-100, the only major protein of LDL, we have identified over 100 different human antibodies reacting against aldehyde-modified apoB-100 sequences. IgM antibody titer levels decreased with age and were associated with the intima-media thickness of the carotid artery in subjects younger than 60 years. There were also inverse associations between IgM levels and oxidized LDL in plasma. In prospective clinical studies, antibody levels against several aldehyde-modified apoB-100 sites were associated with cardiovascular disease in this age group. Whether this immune response is adaptive (protective) or maladaptive (causal) in atherosclerosis requires further investigation. Conclusions— We have characterized a large number of epitopes within the apoB-100 component of oxidized LDL that provoke an immune response in humans. These findings will make it possible to study the role of immune responses against specific sites in oxidized LDL and to determine whether these immune responses influence the risk for future cardiac events.
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