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  • 1
    Online Resource
    Online Resource
    Transforming growth factor-β2 is associated with atherosclerotic plaque stability and lower risk for cardiovascular events
    Oxford University Press (OUP) ; 2023
    In:  Cardiovascular Research Vol. 119, No. 11 ( 2023-09-05), p. 2061-2073
    Details
    In: Cardiovascular Research, Oxford University Press (OUP), Vol. 119, No. 11 ( 2023-09-05), p. 2061-2073
    Abstract: Transforming growth factor-beta (TGF-β) exists in three isoforms TGF-β1, -β2, and -β3. TGF-β1 has been suggested to be important for maintaining plaque stability, yet the role of TGF-β2 and -β3 in atherosclerosis remains to be investigated. This study explores the association of the three isoforms of TGF-β with plaque stability in the human atherosclerotic disease. Methods and results TGF-β1, -β2, and -β3 proteins were quantified in 223 human carotid plaques by immunoassays. Indications for the endarterectomy were: symptomatic carotid plaque with stenosis & gt;70% or without symptoms and & gt;80% stenosis. Plaque mRNA levels were assessed by RNA sequencing. Plaque components and extracellular matrix were measured histologically and biochemically. Matrix metalloproteinases and monocyte chemoattractant protein-1 (MCP-1) was measured with immunoassays. The effect of TGF-β2 on inflammation and protease activity was investigated in vitro using THP-1 and RAW264.7 macrophages. Patients were followed longitudinally for cardiovascular (CV) events. TGF-β2 was the most abundant isoform and was increased at both protein and mRNA levels in asymptomatic plaques. TGF-β2 was the main determinant separating asymptomatic plaques in an Orthogonal Projections to Latent Structures Discriminant Analysis. TGF-β2 correlated positively to features of plaque stability and inversely to markers of plaque vulnerability. TGF-β2 was the only isoform inversely correlated to the matrix-degrading matrix metalloproteinase-9 and inflammation in the plaque tissue. In vitro, TGF-β2 pre-treatment reduced MCP-1 gene and protein levels as well as matrix metalloproteinase-9 gene levels and activity. Patients with plaques with high TGF-β2 levels had a lower risk to suffer from future CV events. Conclusions TGF-β2 is the most abundant TGF-β isoform in human plaques and may maintain plaque stability by decreasing inflammation and matrix degradation.
    Type of Medium: Online Resource
    ISSN: 0008-6363 , 1755-3245
    URL: Article
    DOI: 10.1093/cvr/cvad079
    RVK:
    WA 15000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 2
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    Low Levels of CD4 + CD28 null T Cells at Baseline Are Associated With First-Time Coronary Events in a Prospective Population-Based Case-Control Cohort
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 40, No. 2 ( 2020-02), p. 426-436
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 40, No. 2 ( 2020-02), p. 426-436
    Abstract: CD4 + CD28 null T cells have been shown to be associated with recurrent coronary events and suggested as potential biomarker and therapeutic target. It is unknown whether CD4 + CD28 null T cells associate with first-time cardiovascular events. We examined CD4 + CD28 null T cells in a prospective population-based cohort and in patients with advanced atherosclerosis. Approach and Results: CD4 + CD28 null T cells were quantified in 272 individuals experiencing a first-time coronary event during up to 17 years of follow-up and 272 age- and sex-matched controls in a case-control study, nested within the population-based Malmö Diet and Cancer study. The highest tertile of CD4 + CD28 null T cells was associated with a lower incidence of first-time coronary events compared with the lowest tertile (odds ratio, 0.48 [95% CI, 0.29–0.79], P =0.004) when adjusting for Framingham risk factors. This association remained significant for events recorded after 〉 9 years of follow-up, when most coronary events occurred, but not during the first 9 years of follow-up, despite similar odds ratio. Additionally, we analyzed CD4 + CD28 null T cells in 201 patients with advanced atherosclerosis undergoing carotid endarterectomy. The adjusted hazard ratio for cardiovascular events in patients with advanced atherosclerosis was 2.11 (95% CI, 1.10–4.05, P =0.024), comparing the highest with the lowest CD4 + CD28 null T-cell tertile. Conclusions: Our findings reveal complex associations between CD4 + CD28 null T cells and cardiovascular disease. Although we confirm the reported positive associations with an adverse prognosis in patients with already established disease, the opposite associations with first-time coronary events in the population-based cohort may limit the clinical use of CD4 + CD28 null T cells.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.119.313032
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
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  • 3
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    Dystrophin deficiency reduces atherosclerotic plaque development in ApoE-null mice
    Springer Science and Business Media LLC ; 2015
    In:  Scientific Reports Vol. 5, No. 1 ( 2015-09-08)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2015-09-08)
    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.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/srep13904
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2015
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  • 4
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    Plaque Vulnerability Index Predicts Cardiovascular Events: A Histological Study of an Endarterectomy Cohort
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Journal of the American Heart Association Vol. 10, No. 15 ( 2021-08-03)
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 10, No. 15 ( 2021-08-03)
    Abstract: The balance between stabilizing and destabilizing atherosclerotic plaque components is used in experimental studies and in imaging studies to identify rupture prone plaques. However, we lack the evidence that this balance predicts future cardiovascular events. Here we explore whether a calculated histological ratio, referred to as vulnerability index (VI), can predict patients at higher risk to suffer from future cardiovascular events. Methods and Results Carotid plaques and clinical information from 194 patients were studied. Tissue sections were used for histological analysis to calculate the VI (CD68 [cluster of differentiation 68], alpha‐actin, Oil red O, Movat pentachrome, and glycophorin A). Postoperative cardiovascular events were identified through the Swedish National Inpatient Health Register (2005–2013). During the follow‐up (60 months) 45 postoperative cardiovascular events were registered. Patients with a plaque VI in the fourth quartile compared with the first to third quartiles had significantly higher risk to suffer from a future cardiovascular event ( P =0.0002). The VI was an independent predictor and none of the 5 histological variables analyzed separately predicted events. In the 13 patients who underwent bilateral carotid endarterectomy, the VI of the right plaque correlated with the VI of the left plaque and vice versa ( r =0.7, P =0.01). Conclusions Our findings demonstrate that subjects with a high plaque VI have an increased risk of future cardiovascular events, independently of symptoms and other known cardiovascular risk factors . This strongly supports that techniques which image such plaques can facilitate risk stratification for subjects in need of more intense treatment.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.120.021038
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
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  • 5
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    Reduced oxidized LDL in T2D plaques is associated with a greater statin usage but not with future cardiovascular events
    Springer Science and Business Media LLC ; 2020
    In:  Cardiovascular Diabetology Vol. 19, No. 1 ( 2020-12)
    Details
    In: Cardiovascular Diabetology, Springer Science and Business Media LLC, Vol. 19, No. 1 ( 2020-12)
    Abstract: Type 2 diabetes (T2D) patients are at a greater risk of cardiovascular events due to aggravated atherosclerosis. Oxidized LDL (oxLDL) has been shown to be increased in T2D plaques and suggested to contribute to plaque ruptures. Despite intensified statin treatment during the last decade the higher risk for events remains. Here, we explored if intensified statin treatment was associated with reduced oxLDL in T2D plaques and if oxLDL predicts cardiovascular events, to elucidate whether further plaque oxLDL reduction would be a promising therapeutic target. Methods Carotid plaque OxLDL levels and plasma lipoproteins were assessed in 200 patients. Plaque oxLDL was located by immunohistochemistry. Plaque cytokines, cells and scavenger receptor gene expression were quantified by Luminex, immunohistochemistry and RNA sequencing, respectively. Clinical information and events during follow-up were obtained from national registers. Results Plaque oxLDL levels correlated with markers of inflammatory activity, endothelial activation and plasma LDL cholesterol (r = 0.22-0.32 and p ≤ 0.01 for all). T2D individuals exhibited lower plaque levels of oxLDL, sLOX-1(a marker of endothelial activation) and plasma LDL cholesterol (p = 0.001, p = 0.006 and p = 0.009). No increased gene expression of scavenger receptors was identified in T2D plaques. The lower oxLDL content in T2D plaques was associated with a greater statin usage (p = 0.026). Supporting this, a linear regression model showed that statin treatment was the factor with the strongest association to plaque oxLDL and plasma LDL cholesterol (p  〈  0.001 for both). However, patients with T2D more frequently suffered from symptoms and yet plaque levels of oxLDL did not predict cardiovascular events in T2D (findings are summarized in Fig. 1a). Conclusions This study points out the importance of statin treatment in affecting plaque biology in T2D. It also implies that other biological components, beyond oxLDL, need to be identified and targeted to further reduce the risk of events among T2D patients receiving statin treatment.
    Type of Medium: Online Resource
    ISSN: 1475-2840
    URL: Article
    DOI: 10.1186/s12933-020-01189-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2093769-6
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  • 6
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    The proteoglycan mimecan is associated with carotid plaque vulnerability and increased risk of future cardiovascular death
    Elsevier BV ; 2020
    In:  Atherosclerosis Vol. 313 ( 2020-11), p. 88-95
    Details
    In: Atherosclerosis, Elsevier BV, Vol. 313 ( 2020-11), p. 88-95
    Type of Medium: Online Resource
    ISSN: 0021-9150
    URL: Article
    DOI: 10.1016/j.atherosclerosis.2020.09.011
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 80061-2
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  • 7
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    Expression of fibromodulin in carotid atherosclerotic plaques is associated with diabetes and cerebrovascular events
    Elsevier BV ; 2015
    In:  Atherosclerosis Vol. 241, No. 2 ( 2015-08), p. 701-708
    Details
    In: Atherosclerosis, Elsevier BV, Vol. 241, No. 2 ( 2015-08), p. 701-708
    Type of Medium: Online Resource
    ISSN: 0021-9150
    URL: Article
    DOI: 10.1016/j.atherosclerosis.2015.06.023
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2015
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  • 8
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    Increased proteolytic cleavage of osteoglycin is associated with a stable plaque phenotype and lower risk of cardiovascular events
    Elsevier BV ; 2022
    In:  Atherosclerosis Vol. 355 ( 2022-08), p. 8-14
    Details
    In: Atherosclerosis, Elsevier BV, Vol. 355 ( 2022-08), p. 8-14
    Type of Medium: Online Resource
    ISSN: 0021-9150
    URL: Article
    DOI: 10.1016/j.atherosclerosis.2022.06.1025
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 80061-2
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  • 9
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    sTRAIL-R2 (Soluble TNF [Tumor Necrosis Factor]-Related Apoptosis-Inducing Ligand Receptor 2) a Marker of Plaque Cell Apoptosis and Cardiovascular Events
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Stroke Vol. 50, No. 8 ( 2019-08), p. 1989-1996
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 50, No. 8 ( 2019-08), p. 1989-1996
    Abstract: Cellular apoptosis is an important feature in atherosclerosis, contributing to necrotic core formation, and plaque vulnerability. Activation of the death receptor TRAIL-R2 (TNF [tumor necrosis factor]-related apoptosis-inducing ligand receptor 2) through its ligand tumor necrosis factor-relate apoptosis-inducing ligand (TRAIL), induces apoptosis in cells in vitro. sTRAIL-R2 (soluble TRAIL-R2) was recently shown to predict cardiovascular events in healthy individuals. In the present study, we explored if plaque levels of sTRAIL-R2 and sTRAIL reflect plaque apoptosis and vulnerability and if plasma levels of these markers predict future events in subjects with advanced atherosclerosis. Methods— Plasma from 558 patients and 202 carotid plaques from the Carotid Plaque Imaging Project biobank were used. sTRAIL-R2, sTRAIL, and caspase-8 levels were assessed using a Proseek Multiplex CVD 96×96 assay. Active caspase-3 was measured using ELISA to assess plaque apoptosis. Plaque morphology was studied by immunohistochemistry. Inflammatory cytokines were assessed by Luminex. mRNA levels were quantified by RNA sequencing. Monocytes, T cells, B cells, and human coronary artery smooth muscle cells were used to study sTRAIL-R2 and sTRAIL release on cell apoptosis and inflammatory stimuli in vitro. Results— Plaque levels of sTRAIL-R2 and sTRAIL correlated to markers of extrinsic induced apoptosis (caspase-3 and -8). sTRAIL-R2 and sTRAIL protein expression were increased in symptomatic carotid plaques and patients with higher plasma levels of sTRAIL-R2 had a higher risk of future cardiovascular events. sTRAIL-R2 and sTRAIL were released upon activation of the extrinsic apoptosis pathway in vitro. sTRAIL-R2 and sTRAIL correlated with inflammatory cytokines, to CD68 expression and inversely to α-actin in the plaque tissue. Conclusions— The present study shows that sTRAIL-R2 and sTRAIL are associated to human plaque cell apoptosis, plaque inflammatory activity, and with symptomatic carotid plaques. Furthermore, high plasma levels of sTRAIL-R2 in plasma predict, independently, future cardiovascular events in individuals with manifest atherosclerotic disease.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.119.024379
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
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    detail.hit.zdb_id: 1467823-8
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  • 10
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    Evidence for a protective role of placental growth factor in cardiovascular disease
    American Association for the Advancement of Science (AAAS) ; 2020
    In:  Science Translational Medicine Vol. 12, No. 572 ( 2020-12-02)
    Details
    In: Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 12, No. 572 ( 2020-12-02)
    Abstract: Placental growth factor (PlGF) is a mitogen for endothelial cells, but it can also act as a proinflammatory cytokine. Because it promotes early stages of plaque formation in experimental models of atherosclerosis and was implicated in epidemiological associations with risk of cardiovascular disease (CVD), PlGF has been attributed a pro-atherogenic role. Here, we investigated whether PlGF has a protective role in CVD and whether elevated PlGF reflects activation of repair processes in response to vascular stress. In a population cohort of 4742 individuals with 20 years of follow-up, high baseline plasma PlGF was associated with increased risk of cardiovascular death, myocardial infarction, and stroke, but these associations were lost or weakened when adjusting for cardiovascular risk factors known to cause vascular stress. Exposure of cultured endothelial cells to high glucose, oxidized low-density lipoprotein (LDL) or an inducer of apoptosis enhanced the release of PlGF. Smooth muscle cells and endothelial cells treated with PlGF small interference RNA demonstrated that autocrine PlGF stimulation plays an important role in vascular repair responses. High expression of PlGF in human carotid plaques removed at surgery was associated with a more stable plaque phenotype and a lower risk of future cardiovascular events. When adjusting associations of PlGF with cardiovascular risk in the population cohort for plasma soluble tumor necrosis factor–related apoptosis–inducing ligand (TRAIL) receptor-2, a biomarker of cellular stress, a high PlGF/TRAIL receptor-2 ratio was associated with a lower risk. Our findings provide evidence for a protective role of PlGF in CVD.
    Type of Medium: Online Resource
    ISSN: 1946-6234 , 1946-6242
    URL: Article
    DOI: 10.1126/scitranslmed.abc8587
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2020
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