| 1. |
- Krivospitskaya, Olesya, 1983-, et al.
(författare)
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A CYP26B1 polymorphism enhances retinoic acid catabolism and may aggravate atherosclerosis
- 2012
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Ingår i: Molecular Medicine. - New York, USA : The Feinstein Institute for Medical Research. - 1076-1551 .- 1528-3658. ; 18:1, s. 712-718
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Tidskriftsartikel (refereegranskat)abstract
- All-trans retinoic acid, controlled by CYP26 enzymes, potentially has beneficial effects in atherosclerosis treatment. This study investigates CYP26B1 in atherosclerosis and effects of a genetic polymorphism in CYP26B1 on retinoid catabolism. We found that CYP26B1 mRNA was induced by retinoic acid in human atherosclerotic arteries and CYP26B1 and the macrophage marker CD68 co-localized in human atherosclerotic lesions. In mice, Cyp26B1 mRNA was higher in atherosclerotic than normal arteries. Databases were queried for non-synonymous CYP26B1 SNPs and rs2241057 selected for further studies. Constructs of the CYP26B1 variants were created and used for production of purified proteins and transfection of macrophage-like cells. The minor variant catabolized retinoic acid with significantly higher efficiency, indicating that rs2241057 is functional and suggesting reduced retinoid availability in tissues with the minor variant. rs2241057 was investigated in a Stockholm Coronary Atherosclerosis Risk Factor (SCARF) subgroup. The minor allele was associated with slightly larger lesions as determined by angiography. In summary, this study identifies the first CYP26B1 polymorphism that alters CYP26B1 capacity to metabolize retinoic acid. CYP26B1 was expressed in macrophage-rich areas of human atherosclerotic lesions, induced by retinoic acid and increased in murine atherosclerosis. Taken together, the results indicate that CYP26B1 capacity is genetically regulated and suggest that local CYP26B1 activity may influence atherosclerosis.
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| 2. |
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| 3. |
- Neumayer, Sabine M., et al.
(författare)
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Surface Chemistry Controls Anomalous Ferroelectric Behavior in Lithium Niobate
- 2018
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Ingår i: ACS Applied Materials and Interfaces. - : American Chemical Society (ACS). - 1944-8244 .- 1944-8252. ; 10:34, s. 29153-29160
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Tidskriftsartikel (refereegranskat)abstract
- Polarization switching in ferroelectric materials underpins a multitude of applications ranging from nonvolatile memories to data storage to ferroelectric lithography. While traditionally considered to be a functionality of the material only, basic theoretical considerations suggest that switching is expected to be intrinsically linked to changes in the electrochemical state of the surface. Hence, the properties and dynamics of the screening charges can affect or control the switching dynamics. Despite being recognized for over 50 years, analysis of these phenomena remained largely speculative. Here, we explore polarization switching on the prototypical LiNbO3 surface using the combination of contact mode Kelvin probe force microscopy and chemical imaging by time-of-flight mass-spectrometry and demonstrate pronounced chemical differences between the domains. These studies provide a consistent explanation to the anomalous polarization and surface charge behavior observed in LiNbO3 and point to new opportunities in chemical control of polarization dynamics in thin films and crystals via control of surface chemistry, complementing traditional routes via bulk doping, and substrate-induced strain and tilt systems.
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| 4. |
- Ovchinnikova, Olga
(författare)
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Immune mechanisms behind plaque vulnerability : experimental and clinical studies
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Physical disruption of atherosclerotic plaques causes many acute thrombotic complications such as myocardial infarction and stroke. The resistance of the atherosclerotic plaque to disruption depends in part on the integrity of its fibrous cap, which prevents contact between the highly thrombogenic lipid core and the circulating blood. The fibrillar collagens types I and III synthesized by smooth muscle cells (SMCs) largely determine the tensile strength of the cap. Sites of plaque rupture display signs of active inflammation that can impair plaque stability. Macrophages and mast cells release a set of collagen-degrading enzymes. Additional possible mechanisms include inhibited expression of procollagen genes and induction of death or reduced renewal of the collagen-producing SMC population, both phenomena promoted by T cell-derived interferon-? (IFN?). However, little attention has been given to the post-translational modification of collagen fibers in the fibrous caps. It is known that efficient extracellular cross-linking of collagen catalyzed by the enzyme lysyl oxidase (LOX) confers biomechanical properties and proteolytic resistance of the mature collagen fiber. Thus, failure of collagen maturation may lead to a defective extracellular matrix in the fibrous cap. Using atherosclerosis-prone mice and samples of human carotid endarterectomies, we investigated whether pro- and anti-inflammatory mediators can affect the LOX-dependent collagen maturation in atherosclerotic lesions, thus leading to plaque weakening. To study the effect of T cell-driven inflammation, we used genetically modified mice with hypercholesterolemia and disrupted TGFß signaling in T cells (Apoe-/- x CD4dnTßRII). These mice developed larger atherosclerotic lesions with augmented levels of IFN?, increased numbers of activated macrophages and, importantly, impaired maturation of collagen fibers, consistent with a vulnerable phenotype (Paper I). Analysis of mRNA and protein content showed a significant decrease of LOX in aortae of Apoe-/- x CD4dnTßRII mice. T cell-driven inflammation in these mice provoked a limited selective increase in the expression of proteinases that degrade the extracellular matrix, but no increase in collagen fragmentation was detected. Therefore, we concluded that exaggerated T cell-driven inflammation limits the extracellular maturation of collagen in the atherosclerotic plaque. The stability of atherosclerotic lesions was investigated in Apoe-/- mice after treatment with osteoprotegerin (OPG), a cytokine of the TNFR superfamily and a circulating decoy receptor for the receptor activator of nuclear factor ?B ligand (RANKL) (Paper II). Treatment with OPG facilitated accumulation of SMCs and increased formation of mature collagen fibers within the lesions of Apoe-/- mice. Aortic mRNA level of LOX was also upregulated in treated animals. In cell culture studies, OPG promoted proliferation of rat aortic SMCs. Therefore, we suggested that osteoprotegerin may be a possible mediator of lesion stabilization. We further investigated if a similar pattern as that obtained in the animal experiments could also be found in the human disease (Paper III). We were able to detect LOX protein in SMC- and collagen-rich areas of human carotid lesions. A higher LOX mRNA and protein were associated with a more stable phenotype of the plaques. Examination of gene expression in plaques revealed a positive correlation between mRNA expression of LOX and mRNA for OPG, and a negative correlation between LOX mRNA and markers of inflammation. This data suggests that LOX may contribute to the stabilization of human atherosclerotic lesions and that its expression is controlled by inflammation. In paper IV we reported that mRNA and protein content of 5-lipoxygenase activating protein (FLAP) were highly upregulated in aortae of Apoe-/- x CD4dnTßRII mice compared with Apoe-/- littermates. FLAP immunoreactive protein co-localized with CD68+ macrophages. Augmented ex vivo formation of leukotriene B4 in aortae of transgenic mice further supported functional significance of the increased level of FLAP. Treatment with the FLAP-inhibitor MK-886 not only decreased the number of CD3+ cells in lesions and IFN? mRNA levels in aortae of Apoe-/- x CD4dnTßRII mice, but, most importantly, significantly reduced atherosclerotic lesion size. Although FLAP inhibition did not have any significant effect on collagen synthesis, it can be considered as a possible therapeutic tool to stabilize the plaque by reducing the degree of local inflammation. In summary, the findings of this thesis identify extracellular maturation of collagen, catalyzed by LOX, as important in maintaining the stability of the fibrous cap in the atherosclerotic lesion. The process of collagen maturation is regulated by pro- and anti-inflammatory mediators within the plaque, and it may serve as a target for development of new diagnostic and therapeutic tools.
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| 5. |
- Ovchinnikova, Olga, et al.
(författare)
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Osteoprotegerin promotes fibrous cap formation in atherosclerotic lesions of ApoE-deficient mice--brief report.
- 2009
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 29:10, s. 1478-1480
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Osteoprotegerin (OPG) is a tumor necrosis factor receptor-related cytokine, initially found to inhibit osteoclastogenesis. In the present study we investigated the effect of OPG treatment on atherosclerosis. METHODS AND RESULTS: Hypercholesterolemic apoe(-/-) mice were treated with recombinant 15 mg/kg OPG or vehicle injections twice a week for 10 consecutive weeks. Mice treated with OPG showed increased amounts of smooth muscle cells and collagen within the atherosclerotic lesions. OPG treatment did not affect atherosclerotic lesion size (8.2% versus 7.6%) or total vessel area but led to a 250% increase in lesion collagen, formation of mature collagen fibers in subendothelial fibrous caps, and upregulated mRNA for lysyl oxidase that promotes collagen crosslinking. In cell culture studies, OPG promoted cell proliferation in rat aortic smooth muscle cells. In contrast, OPG treatment did not affect markers of vascular or systemic inflammation. CONCLUSIONS: OPG treatment promotes smooth muscle accumulation, collagen fiber formation, and development of fibrous caps but does not affect inflammatory properties of atherosclerotic lesions. Its effects may contribute to plaque stabilization.
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| 6. |
- Ovchinnikova, Olga, et al.
(författare)
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T-Cell Activation Leads to Reduced Collagen Maturation in Atherosclerotic Plaques of Apoe−/− Mice
- 2009
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Ingår i: American Journal of Pathology. - : Elsevier. - 0002-9440 .- 1525-2191. ; 174:2, s. 693-700
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Tidskriftsartikel (refereegranskat)abstract
- Rupture of the collagenous, fibrous cap of an atherosclerotic plaque commonly causes thrombosis. Activated immune cells can secrete mediators that jeopardize the integrity of the fibrous cap. This study aimed to determine the relationship between T-cell-mediated inflammation and collagen turnover in a mouse model of experimental atherosclerosis. Both Apoe(-/-) x CD4dnT beta RII mice with defective transforming growth factor-beta receptors in T cells (and hence released from tonic suppression of T-cell activation) and lesion size-matched Apoe(-/-) mice were used. Picrosirius red staining showed a lower content of thick mature collagen fibers in lesions of Apoe(-/-) x CD4dnT beta RII mice, although both groups had similar levels of procollagen type I or M mRNA and total collagen content in lesions. Analysis of both gene expression and protein content showed a significant decrease of lysyl oxidase, the extracellular enzyme needed for collagen cross-linking, in aortas of Apoe(-/-) - CD4dnT beta RII mice. T-cell-driven inflammation provoked a selective and limited increase in the expression of proteinases that catabolize the extracellular matrix. Atheromata of Apoe(-/-) - CD4dnT beta RII mice had increased levels of matrix metalloproteinase-13 and cathepsin S mRNAs and of the active form of cathepsin S protein but no increase was detected in collagen fragmentation. our results suggest that exaggerated T-cell-driven inflammation limits collagen maturation in the atherosclerotic plaque while having little effect on collagen degradation.
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