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  • 1
    Online Resource
    Online Resource
    Neutrophil Elastase-Derived Fibrin Degradation Products Indicate Presence of Abdominal Aortic Aneurysms and Correlate with Intraluminal Thrombus Volume
    Georg Thieme Verlag KG ; 2018
    In:  Thrombosis and Haemostasis Vol. 118, No. 02 ( 2018), p. 329-339
    Details
    In: Thrombosis and Haemostasis, Georg Thieme Verlag KG, Vol. 118, No. 02 ( 2018), p. 329-339
    Abstract: Background The intraluminal thrombi (ILT) of abdominal aortic aneurysms (AAA) contain neutrophils, which can secrete elastase. We evaluated whether plasma neutrophil elastase-derived cross-linked fibrin degradation products (E-XDP) could reveal the presence, size and mechanical stress of AAAs and its ILTs. Methods E-XDP and D-dimer were measured in plasma from 37 male patients with AAA and 42 male controls. The ILT volumes of the AAAs and any coexisting aneurysms could be measured in 29 patients and finite element analysis was performed to estimate mechanical stress of the ILT. E-XDP, neutrophil elastase and neutrophil marker CD66acd were evaluated in aortic tissue with immunohistochemistry (IHC). The association between ILT volume and E-XDP was validated in a separate cohort (n = 51). Results E-XDP levels were elevated in patients with AAA compared with controls (p = 5.8e-13), indicated AAA with 98% sensitivity, 86% specificity and increased with presence of coexisting aneurysms. The association between AAA and increased E-XDP was independent of smoking, comorbidities and medication. E-XDP correlated with volume of all ILTs (r = 0.76, p = 4.5e-06), mean ILT stress (r = 0.46, p = 0.013) and the volume of the AAA-associated ILT (r = 0.64, p = 0.00017). E-XDP correlated stronger with ILT volume compared with D-dimer (r = 0.76 vs. r = 0.64, p = 0.018). The correlation between E-XDP and ILT volume was validated in the separate cohort (r = 0.53, p = 7.6e-05). IHC revealed E-XDP expression in the ILT, spatially related to neutrophil elastase and neutrophils. Conclusion E-XDP is a marker of the presence of AAA and coexisting aneurysms as well as the volume and mechanical stress of the ILT.
    Type of Medium: Online Resource
    ISSN: 0340-6245 , 2567-689X
    URL: Article
    DOI: 10.1160/TH17-05-0348
    Language: English
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2018
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  • 2
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    Phenotypic Modulation of Smooth Muscle Cells in Atherosclerosis Is Associated With Downregulation of LMOD1, SYNPO2, PDLIM7, PLN , and SYNM
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 36, No. 9 ( 2016-09), p. 1947-1961
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. 9 ( 2016-09), p. 1947-1961
    Abstract: Key augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems biology approach to examine suppressed molecular signatures, with the hypothesis that they may provide insight into mechanisms contributing to plaque stability. Approach and Results— Muscle contraction, muscle development, and actin cytoskeleton were the most downregulated pathways (false discovery rate=6.99e-21, 1.66e-6, 2.54e-10, respectively) in microarrays from human carotid plaques (n=177) versus healthy arteries (n=15). In addition to typical smooth muscle cell (SMC) markers, these pathways also encompassed cytoskeleton-related genes previously not associated with atherosclerosis. SYNPO2, SYNM, LMOD1, PDLIM7 , and PLN expression positively correlated to typical SMC markers in plaques (Pearson r 〉 0.6, P 〈 0.0001) and in rat intimal hyperplasia ( r 〉 0.8, P 〈 0.0001). By immunohistochemistry, the proteins were expressed in SMCs in normal vessels, but largely absent in human plaques and intimal hyperplasia. Subcellularly, most proteins localized to the cytoskeleton in cultured SMCs and were regulated by active enhancer histone modification H3K27ac by chromatin immunoprecipitation-sequencing. Functionally, the genes were downregulated by PDGFB (platelet-derived growth factor beta) and IFNg (interferron gamma), exposure to shear flow stress, and oxLDL (oxidized low-density lipoprotein) loading. Genetic variants in PDLIM7, PLN , and SYNPO2 loci associated with progression of carotid intima-media thickness in high-risk subjects without symptoms of cardiovascular disease (n=3378). By eQTL (expression quantitative trait locus), rs11746443 also associated with PDLIM7 expression in plaques. Mechanistically, silencing of PDLIM7 in vitro led to downregulation of SMC markers and disruption of the actin cytoskeleton, decreased cell spreading, and increased proliferation. Conclusions— We identified a panel of genes that reflect the altered phenotype of SMCs in vascular disease and could be early sensitive markers of SMC dedifferentiation.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.116.307893
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 1494427-3
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  • 3
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    Abstract 173: Proprotein Convertase Subtilisin/Kexin Type 6 is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 36, No. suppl_1 ( 2016-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. suppl_1 ( 2016-05)
    Abstract: Proprotein convertases (PCSKs) process matrix metalloproteases (MMPs) and cytokines. Apart from PCSK9, the role of these enzymes in vascular disease is largely unknown. Previously, we demonstrated upregulation of PCSK6 in carotid atherosclerosis, primarily localized to smooth muscle cells (SMCs) and positively correlated to inflammation, extracellular matrix remodeling and cytokines. Here, we extended these findings to determine the role of PCSK6 in vascular development and disease. Increased expression of PCSK6 in vascular disease was validated by microarrays from two non-overlapping cohorts of carotid plaques vs. non-atherosclerotic arteries (n=50 patients and n=32 patients, p 〈 0.0001), as well as abdominal (AAA, n=14, p 〈 0.0001) and thoracic aortic aneurysms (TAA, n=244, p=0.012). By eQTL, variants in the PCSK6 gene were found to influence it’s expression in both plaques and aneurysms. Among these, rs6598465 also showed association with maximum progression of carotid intima-media thickness in high-risk coronary artery disease subjects (n=3388, p=0.037). By IHC, PCSK6 localized mainly to SMCs in the fibrous cap and neovessels in atherosclerotic, AAA and TAA tissues. In mouse-, rat-, and human intimal hyperplasia, PCSK6 was expressed in proliferating SMCs. By microarrays, after rat carotid balloon injury there was an early downregulation of PCSK6 followed by an upregulation in later phases during SMC activation, as well as positive correlation to PDGFB and IGF1 (Spearman r 〉 0.7, p 〈 0.0001) and to MMP2 and MMP14 (r 〉 0.5, p 〈 0.0001). In zebrafish embryos, PCSK6 localized to heart and vasculature and its ablation caused defective peripheral vascular patterning with cerebral and myocardial hemorrhage. PCSK6 -/- mice did not present an obvious vascular phenotype but showed reduced intimal hyperplasia compared to wild-type mice after carotid artery ligation (p=0.015). In vitro, PCSK6 overexpression markedly increased SMC migration upon PDGFBB stimulation (p 〈 0.0001). The present study establishes PCSK6 as a key modulator of SMC function in vascular disease and demonstrates a functional link between PCSK6 expression and SMC migration in vascular remodeling.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.36.suppl_1.173
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 1494427-3
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  • 4
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    Abstract 420: Proprotein Convertase Subtilisin/Kexin 6 Is Involved In Lipid Metabolism In Liver
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 42, No. Suppl_1 ( 2022-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 42, No. Suppl_1 ( 2022-05)
    Abstract: Introduction: PCSK6 is a protease that activates cytokines and growth factors and strongly enriched in healthy human liver, however its function in this context has not been explored. We have previously shown that PCSK6 is induced in atherosclerotic plaques from patients with symptoms of stroke and important for regulating several cell types in this context. Here, we aimed to investigate the role of PCSK6 in lipid metabolism in liver, particularly in the context of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Methods: We used publically available datasets and several atherosclerosis biobanks to investigate the expression of PCSK6 in healthy and diseased human tissues. In addition, we used full Pcsk6 -/- mice as well as liver specific conditional Pcsk6 -/- knockout mice compared to littermate controls, to investigate the effects of PCSK6 ablation on lipid metabolism. Results: Genetic analyses of the PCSK6 locus identified a variant, rs7181043, that was significantly associated with PCSK6 mRNA expression in healthy human adipose tissue, liver and in atherosclerotic plaques. The same variant was associated specifically with plaque fat content and atherosclerotic patient’s plasma LDL levels. In addition, PCSK6 mRNA expression in plaques was positively correlated with total plasma cholesterol and LDL levels in atherosclerotic patients as well as lipid metabolism associated pathways within the carotid plaque. Microarray comparison of the livers from Pcsk6 -/- mice and controls showed that VLDL particle assembly was one of the upregulated processes. I n vivo studies showed that Pcsk6 -/- mice have higher plasma cholesterol and LPL levels at baseline compared to controls, and lower levels of LDLR in their liver. These findings were further confirmed in liver specific conditional knockouts. Preliminary results show that liver specific knockout mice develop increased liver steatosis and fibrosis on a modified western diet. Conclusions: Our data suggests that PCSK6 is involved in cholesterol and metabolic control in liver. Breeding of liver specific Pcsk6 knockout mice on an ApoE -/- background is currently ongoing and will provide insight into the role of liver PCSK6 in atherosclerosis and NAFLD development.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.42.suppl_1.420
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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  • 5
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    NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Journal of the American Heart Association Vol. 5, No. 5 ( 2016-05-06)
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 5, No. 5 ( 2016-05-06)
    Abstract: The NLR family, pyrin domain containing 3 ( NLRP 3) inflammasome is an interleukin ( IL )‐1β and IL ‐18 cytokine processing complex that is activated in inflammatory conditions. The role of the NLRP 3 inflammasome in the pathogenesis of atherosclerosis and myocardial infarction is not fully understood. Methods and Results Atherosclerotic plaques were analyzed for transcripts of the NLRP 3 inflammasome, and for IL ‐1β release. The Swedish First‐ever myocardial Infarction study in Ac‐county ( FIA ) cohort consisting of DNA from 555 myocardial infarction patients and 1016 healthy individuals was used to determine the frequency of 4 single nucleotide polymorphisms ( SNP s) from the downstream regulatory region of NLRP 3. Expression of NLRP 3, Apoptosis‐associated speck‐like protein containing a CARD ( ASC ), caspase‐1 ( CASP 1), IL 1B, and IL 18 mRNA was significantly increased in atherosclerotic plaques compared to normal arteries. The expression of NLRP 3 mRNA was significantly higher in plaques of symptomatic patients when compared to asymptomatic ones. CD 68‐positive macrophages were observed in the same areas of atherosclerotic lesions as NLRP 3 and ASC expression. Occasionally, expression of NLRP 3 and ASC was also present in smooth muscle cells. Cholesterol crystals and ATP induced IL ‐1β release from lipopolysaccharide‐primed human atherosclerotic lesion plaques. The minor alleles of the variants rs4266924, rs6672995, and rs10733113 were associated with NLRP 3 mRNA levels in peripheral blood mononuclear cells but not with the risk of myocardial infarction. Conclusions Our results indicate a possible role of the NLRP 3 inflammasome and its genetic variants in the pathogenesis of atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.115.003031
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 2653953-6
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  • 6
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    Transcriptomic profiling of experimental arterial injury reveals new mechanisms and temporal dynamics in vascular healing response
    Elsevier BV ; 2020
    In:  JVS-Vascular Science Vol. 1 ( 2020), p. 13-27
    Details
    In: JVS-Vascular Science, Elsevier BV, Vol. 1 ( 2020), p. 13-27
    Type of Medium: Online Resource
    ISSN: 2666-3503
    URL: Article
    DOI: 10.1016/j.jvssci.2020.01.001
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 3061185-4
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  • 7
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    Abstract 318: Matrix Metalloproteinase 12 is Causally Implicated in Cardiovascular Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 36, No. suppl_1 ( 2016-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. suppl_1 ( 2016-05)
    Abstract: Recent evidence suggests that single nucleotide polymorphisms (SNPs) in the matrix metalloproteinase (MMP) gene cluster located at chromosome 11q22.3 are associated with large-vessel stroke. In the present study, we evaluated and extended the reported association by examining the relationship between MMPs and vascular disease in both clinical and experimental samples. Plasma concentrations of MMP-1, MMP-3, MMP-7, MMP-10 and MMP-12 were measured in 3 394 subjects with high-risk for cardiovascular disease (CVD) using the Olink ProSeek CVD array. Plasma MMP-12 concentration showed association with incident cardiovascular events (199 events over 36 months) and intima-media thickness progression over time (p=3.6x10 -5 ). The SNP variant rs1892971 was strongly associated with plasma MMP-12 concentration (p=8x10 -29 ) and weakly with susceptibility to coronary heart disease in the CardiogramplusC4D consortium study (p=8.8x10 -5 ). The same SNP was also significantly associated with MMP-12 gene expression in peripheral blood mononuclear cells using microarrays from patients with carotid atherosclerosis (n=96; p=1.8x10 -4 ). Expression of MMP-12 was strongly increased in carotid plaques (n=127) compared with undiseased arteries (n=10; p 〈 0.0001) and in plaques from symptomatic (n=87) compared to asymptomatic patients (n=40; p=0.03) and localised to CD68+ macrophages. Using proximity ligation assay MMP-12 and elastin was demonstrated to co-interact in plaques in situ, particularly in regions with moderate to strong MMP-12 expression. Silencing of MMP-12 using siRNA in differentiated THP-1 cells indicated that MMP-12 has a role in macrophage migration. In conclusion, our study suggests that MMP-12 is a causal factor in CVD that is highly upregulated in human atherosclerotic plaques where it interacts with elastin and appears to enhance macrophage invasion.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.36.suppl_1.318
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
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  • 8
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    Abstract 467: PCSK6 Is Upregulated in Vascular Diseases Characterized by Inflammation and Smooth Muscle Cell Proliferation
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 34, No. suppl_1 ( 2014-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. suppl_1 ( 2014-05)
    Abstract: Recently we demonstrated upregulation of the proprotein convertase PCSK6 in a large cohort of human carotid atherosclerotic plaques (n=127) compared to normal arteries and in symptomatic vs. asymptomatic lesions. PCSK6 was localized to smooth muscle cells (SMCs) in the fibrous cap and showed a positive correlation to markers of inflammation, extracellular matrix remodeling and cytokines. Here, we aimed at elucidating the role of this protease in vascular disease by examining its expression in different human pathologies and in animal models. Increased expression of PCSK6 in vascular diseases was validated in public microarray datasets and other available human cohorts. PCSK6 was upregulated in carotid atherosclerotic plaques vs. controls (n=32 patients, p 〈 0.0001), as well as in abdominal aortic aneurysm (AAA) vs. normal tissue (n=14, p 〈 0.0001) and in thoracic aortic aneurysm (TAA) tissue from bicuspid vs. tricuspid patients (n=244, p=0.012). By eQTL analyses, several SNPs in the PCSK6 genomic region were shown to influence its expression in carotid plaques and TAA tissue. Among these, rs6598465 showed a mild association to progression of maximum intima-media thickness in the left and right arteries in a separate cohort of high-risk coronary artery disease subjects (n=3400, p=0.037). By immunohistochemistry, PCSK6 localized mainly to SMCs in carotid plaques, AAA and TAA tissue, but was also found to be expressed by CD68 and CD163+ macrophages. Investigation of mouse, rat and human artery tissues with pronounced intimal hyperplasia revealed strong expression of PCSK6 in proliferating SMCs. In rat carotid artery balloon injury, PCSK6 was downregulated in the early phases after injury mostly defined by inflammatory response, while upregulated in later phases with prominent SMC activation, and consistently localized in SMCs. Expression of PCSK6 in this model was strongly positively correlated solely to PDGFB and IGF1 (p 〈 0.0001), cytokines known to induce SMC proliferation. We established a functional link between elevated expression of PCSK6 and vascular diseases characterized by inflammation and SMC proliferation. Further investigations in vitro are necessary to provide mechanistic insight into the role of this protease in vascular disease.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.34.suppl_1.467
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
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  • 9
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    Differential expression of sex hormone receptors in abdominal aortic aneurysms
    Elsevier BV ; 2017
    In:  Maturitas Vol. 96 ( 2017-02), p. 39-44
    Details
    In: Maturitas, Elsevier BV, Vol. 96 ( 2017-02), p. 39-44
    Type of Medium: Online Resource
    ISSN: 0378-5122
    URL: Article
    DOI: 10.1016/j.maturitas.2016.11.005
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2017
    detail.hit.zdb_id: 2008054-2
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  • 10
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    Vessel wall morphology is equivalent for different artery types and localizations of advanced human aneurysms
    Springer Science and Business Media LLC ; 2017
    In:  Histochemistry and Cell Biology Vol. 148, No. 4 ( 2017-10), p. 425-433
    Details
    In: Histochemistry and Cell Biology, Springer Science and Business Media LLC, Vol. 148, No. 4 ( 2017-10), p. 425-433
    Type of Medium: Online Resource
    ISSN: 0948-6143 , 1432-119X
    URL: Article
    DOI: 10.1007/s00418-017-1575-3
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 1398345-3
    SSG: 12
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