| 11. |
- Shami, Annelie, et al.
(author)
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Dystrophin deficiency reduces atherosclerotic plaque development in ApoE-null mice.
- 2015
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Journal article (peer-reviewed)abstract
- Dystrophin of the dystrophin-glycoprotein complex connects the actin cytoskeleton to basement membranes and loss of dystrophin results in Duchenne muscular dystrophy. We have previously shown injury-induced neointima formation of the carotid artery in mice with the mdx mutation (causing dystrophin deficiency) to be increased. To investigate the role of dystrophin in intimal recruitment of smooth muscle cells (SMCs) that maintains plaque stability in atherosclerosis we applied a shear stress-modifying cast around the carotid artery of apolipoprotein E (ApoE)-null mice with and without the mdx mutation. The cast induces formation of atherosclerotic plaques of inflammatory and SMC-rich/fibrous phenotypes in regions of low and oscillatory shear stress, respectively. Unexpectedly, presence of the mdx mutation markedly reduced the development of the inflammatory low shear stress plaques. Further characterization of the low shear stress plaques in ApoE-null mdx mice demonstrated reduced infiltration of CD3(+) T cells, less laminin and a higher SMC content. ApoE-null mdx mice were also found to have a reduced fraction of CD3(+) T cells in the spleen and lower levels of cytokines and monocytes in the circulation. The present study is the first to demonstrate a role for dystrophin in atherosclerosis and unexpectedly shows that this primarily involves immune cells.
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| 12. |
- Shami, Annelie, et al.
(author)
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Expression of fibromodulin in carotid atherosclerotic plaques is associated with diabetes and cerebrovascular events.
- 2015
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In: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 241:2, s. 701-708
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Journal article (peer-reviewed)abstract
- The small leucine-rich proteoglycans fibromodulin and lumican are functionally related extracellular matrix proteins involved in the regulation of collagen fiber formation. Fibromodulin-deficient apolipoprotein E-null mice have decreased vascular retention of lipids and reduced development of atherosclerosis suggesting that fibromodulin may influence the disease process. The aim of the present study was to investigate if fibromodulin and lumican are expressed in human carotid plaques and to determine if their expression is associated with the occurrence of preoperative symptoms and with risk for postoperative cardiovascular events.
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| 13. |
- Shami, Annelie
(author)
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Fibromodulin and Dystrophin in Atherosclerosis: Novel roles for extracellular matrix in plaque development
- 2014
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Doctoral thesis (other academic/artistic)abstract
- Cardiovascular disease represents nearly half the cases of noncommunicable diseases worldwide and is the leading global cause of death. The main underlying cause is atherosclerosis, and in atherosclerotic plaque progression the structure, composition and integrity of a dynamic extracellular matrix (ECM) is one very important factor. This thesis discusses the importance of the connection between the ECM and cells for atherosclerotic lesion development. It also tests the hypothesis that changes in this connection – whether through a modified collagenous ECM, or modification in a cellular protein directly linking cells to ECM components – have a significant impact on atherosclerotic plaque structure and stability. Fibromodulin is a small leucine-rich repeat proteoglycan of the ECM involved in the regulation of collagen fiber synthesis. In the fibrous murine atherosclerotic plaque, we found collagen fibrils synthesized in the absence of fibromodulin to be thicker and more heterogeneous, compared to fibrils generated in the control mouse. Murine plaques with an inflammatory phenotype, with a fibromodulin-deficient ECM, were also smaller with decreased lipid accumulation, whereas cell proliferation was increased. In addition, we show, for the first time, that high fibromodulin expression in the most stenotic region of a human carotid artery plaque is found in plaques from symptomatic patients, and in patients with diabetes. Fibromodulin expressed in human plaques co-localize with Oil Red O-staining and correlates with the area stained for lipids (quantified as percentage). Fibromodulin also correlates with the pro-inflammatory cytokines MIP-1β and sCD40L, as well as with VEGF and inversely with the anti-inflammatory cytokine IL-10. Dystrophin, and the dystrophin-glycoprotein complex (DGC), link the actin cytoskeleton to the basement membrane. This thesis provides novel data on dystrophin deficiency, as illustrated by the mdx mouse. The absence of dystrophin stimulates neointimal hyperplasia, but inhibits atherosclerotic lesion development driven by lipid-retention. In the mdx-mouse, laminin expression is decreased in the endothelium of atherosclerotic lesions with an inflammatory phenotype, suggesting that altered endothelial cell function and an abnormal basement membrane may be a possible explanation for the attenuated plaque development. In summary, this thesis shows that collagen structure and remodeling affects the growth, development and composition of atherosclerotic lesions, on the one hand promoting mechanical stability, and on the other hand affecting lipid accumulation and inflammation. In addition, growth of vascular lesions can be inhibited or promoted by a functional connection between cells and the ECM mediated by dystrophin and the DGC.
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| 14. |
- Shami, Annelie, et al.
(author)
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Fibromodulin Deficiency Reduces Low-Density Lipoprotein Accumulation in Atherosclerotic Plaques in Apolipoprotein E-Null Mice.
- 2012
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In: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636.
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The aim of this study was to analyze how an altered collagen structure affects development of atherosclerotic plaques. METHODS AND RESULTS: Fibromodulin-null mice develop an abnormal collagen fibril structure. In apolipoprotein E (ApoE)-null and ApoE/fibromodulin-null mice, a shear stress-modifying carotid artery cast induced formation of atherosclerotic plaques of different phenotypes; inflammatory in low-shear stress regions and fibrous in oscillatory shear stress regions. Electron microscopy showed that collagen fibrils were thicker and more heterogeneous in oscillatory shear stress lesions from ApoE/fibromodulin-null mice. Low-shear stress lesions were smaller in ApoE/fibromodulin-null mice and contained less lipids. Total plaque burden in aortas stained en face with Oil Red O, as well as lipid accumulation in aortic root lesions, was also decreased in ApoE/fibromodulin-null mice. In addition, lipid accumulation in RAW264.7 macrophages cultured on fibromodulin-deficient extracellular matrix was decreased, whereas levels of interleukin-6 and -10 were increased. Our results show that an abnormal plaque collagen fibril structure can influence atherosclerotic plaque development. CONCLUSIONS: The present findings suggest a more complex role for collagen in plaque stability than previously anticipated, in that it may promote lipid-accumulation and inflammation at the same time as it provides mechanical stability.
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| 15. |
- Shami, Annelie, et al.
(author)
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Glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) drives atherosclerosis in mice and is associated with an unstable plaque phenotype and cerebrovascular events in humans
- 2020
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In: European Heart Journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 41:31, s. 2938-2948
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Journal article (peer-reviewed)abstract
- AIMS: GITR-a co-stimulatory immune checkpoint protein-is known for both its activating and regulating effects on T-cells. As atherosclerosis bears features of chronic inflammation and autoimmunity, we investigated the relevance of GITR in cardiovascular disease (CVD). METHODS AND RESULTS: GITR expression was elevated in carotid endarterectomy specimens obtained from patients with cerebrovascular events (n = 100) compared to asymptomatic patients (n = 93) and correlated with parameters of plaque vulnerability, including plaque macrophage, lipid and glycophorin A content, and levels of interleukin (IL)-6, IL-12, and C-C-chemokine ligand 2. Soluble GITR levels were elevated in plasma from subjects with CVD compared to healthy controls. Plaque area in 28-week-old Gitr-/-Apoe-/- mice was reduced, and plaques had a favourable phenotype with less macrophages, a smaller necrotic core and a thicker fibrous cap. GITR deficiency did not affect the lymphoid population. RNA sequencing of Gitr-/-Apoe-/- and Apoe-/- monocytes and macrophages revealed altered pathways of cell migration, activation, and mitochondrial function. Indeed, Gitr-/-Apoe-/- monocytes displayed decreased integrin levels, reduced recruitment to endothelium, and produced less reactive oxygen species. Likewise, GITR-deficient macrophages produced less cytokines and had a reduced migratory capacity. CONCLUSION: Our data reveal a novel role for the immune checkpoint GITR in driving myeloid cell recruitment and activation in atherosclerosis, thereby inducing plaque growth and vulnerability. In humans, elevated GITR expression in carotid plaques is associated with a vulnerable plaque phenotype and adverse cerebrovascular events. GITR has the potential to become a novel therapeutic target in atherosclerosis as it reduces myeloid cell recruitment to the arterial wall and impedes atherosclerosis progression.
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| 16. |
- Shami, Annelie, et al.
(author)
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Soluble CD40 levels in plasma are associated with cardiovascular disease and in carotid plaques with a vulnerable phenotype
- 2021
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In: Journal of Stroke. - : Korean Stroke Society. - 2287-6391 .- 2287-6405. ; 23:3, s. 367-376
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Journal article (peer-reviewed)abstract
- Background and Purpose CD40 and CD40 ligand (CD40L) are costimulatory molecules of the tumor necrosis factor receptor superfamily and well known for their involvement in inflammatory diseases: atherosclerotic mouse models with disrupted CD40 signalling develop lesions of reduced size with a more stable plaque profile. This study investigated the potential of plasma and intraplaque levels of CD40 and CD40L as markers for cardiovascular disease (CVD) in humans and their association with plaque stability. Methods Soluble CD40 and CD40L (sCD40L) were measured in plasma in 1,437 subjects from The SUrrogate markers for Micro-and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) cohort. Intra-plaque levels of sCD40 and sCD40L were measured in atherosclerotic plaque homogenates from 199 subjects of the Carotid Plaque Imaging Project (CPIP) cohort. Results Both plasma sCD40 and sCD40L levels were elevated in individuals with prevalent stroke, while sCD40 levels also were higher in individuals with a prior acute myocardial infarction. Plasma levels of sCD40 correlated with carotid intima-media thickness and total carotid plaque area and were associated with risk of cardiovascular events over a 3-year follow-up period. Intra-plaque levels of sCD40 and sCD40L were associated with plaque components characteristic for plaque vulnerability and extracellular matrix remodelling. Conclusions Higher plasma sCD40 and sCD40L levels are associated with prevalent CVD. Plasma sCD40 levels also correlate with the severity of carotid atherosclerosis and predict future cardiovascular events, while intra-plaque levels correlate with a vulnerable plaque phenotype. Our findings thus demonstrate that elevated levels of sCD40 and sCD40L are markers of CVD.
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| 17. |
- Sun, Jiangming, et al.
(author)
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Spatial Transcriptional Mapping Reveals Site-Specific Pathways Underlying Human Atherosclerotic Plaque Rupture
- 2023
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In: Journal of the American College of Cardiology. - 0735-1097. ; 81:23, s. 2213-2227
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Journal article (peer-reviewed)abstract
- Background: Atherosclerotic plaque ruptures, triggered by blood flow–associated biomechanical forces, cause most myocardial infarctions and strokes. Objectives: This study aims to investigate the exact location and underlying mechanisms of atherosclerotic plaque ruptures, identifying therapeutic targets against cardiovascular events. Methods: Histology, electron microscopy, bulk and spatial RNA sequencing on human carotid plaques were studied in proximal, most stenotic, and distal regions along the longitudinal blood flow direction. Genome-wide association studies were used to examine heritability enrichment and causal relationships of atherosclerosis and stroke. Associations between top differentially expressed genes (DEGs) and preoperative and postoperative cardiovascular events were examined in a validation cohort. Results: In human carotid atherosclerotic plaques, ruptures predominantly occurred in the proximal and most stenotic regions but not in the distal region. Histologic and electron microscopic examination showed that proximal and most stenotic regions exhibited features of plaque vulnerability and thrombosis. RNA sequencing identified DEGs distinguishing the proximal and most stenotic regions from the distal region which were deemed as most relevant to atherosclerosis-associated diseases as shown by heritability enrichment analyses. The identified pathways associated with the proximal rupture-prone regions were validated by spatial transcriptomics, firstly in human atherosclerosis. Of the 3 top DEGs, matrix metallopeptidase 9 emerged particularly because Mendelian randomization suggested that its high circulating levels were causally associated with atherosclerosis risk. Conclusions: Our findings show plaque site–specific transcriptional signatures associated with proximal rupture-prone regions of carotid atherosclerotic plaques. This led to the geographical mapping of novel therapeutic targets, such as matrix metallopeptidase 9, against plaque rupture.
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