| 1. |
- Rykaczewska, Urszula, et al.
(författare)
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PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling
- 2020
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Ingår i: Circulation Research. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7330 .- 1524-4571. ; 126:5, s. 571-585
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: PCSKs (Proprotein convertase subtilisins/kexins) are a protease family with unknown functions in vasculature. Previously, we demonstrated PCSK6 upregulation in human atherosclerotic plaques associated with smooth muscle cells (SMCs), inflammation, extracellular matrix remodeling, and mitogens. Objective: Here, we applied a systems biology approach to gain deeper insights into the PCSK6 role in normal and diseased vessel wall. Methods and Results: Genetic analyses revealed association of intronic PCSK6 variant rs1531817 with maximum internal carotid intima-media thickness progression in high-cardiovascular risk subjects. This variant was linked with PCSK6 mRNA expression in healthy aortas and plaques but also with overall plaque SMA+ cell content and pericyte fraction. Increased PCSK6 expression was found in several independent human cohorts comparing atherosclerotic lesions versus healthy arteries, using transcriptomic and proteomic datasets. By immunohistochemistry, PCSK6 was localized to fibrous cap SMA+ cells and neovessels in plaques. In human, rat, and mouse intimal hyperplasia, PCSK6 was expressed by proliferating SMA+ cells and upregulated after 5 days in rat carotid balloon injury model, with positive correlation to PDGFB (platelet-derived growth factor subunit B) and MMP (matrix metalloprotease) 2/MMP14. Here, PCSK6 was shown to colocalize and cointeract with MMP2/MMP14 by in situ proximity ligation assay. Microarrays of carotid arteries from Pcsk6(-/-) versus control mice revealed suppression of contractile SMC markers, extracellular matrix remodeling enzymes, and cytokines/receptors. Pcsk6(-/-) mice showed reduced intimal hyperplasia response upon carotid ligation in vivo, accompanied by decreased MMP14 activation and impaired SMC outgrowth from aortic rings ex vivo. PCSK6 silencing in human SMCs in vitro leads to downregulation of contractile markers and increase in MMP2 expression. Conversely, PCSK6 overexpression increased PDGFBB (platelet-derived growth factor BB)-induced cell proliferation and particularly migration. Conclusions: PCSK6 is a novel protease that induces SMC migration in response to PDGFB, mechanistically via modulation of contractile markers and MMP14 activation. This study establishes PCSK6 as a key regulator of SMC function in vascular remodeling.
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| 2. |
- Buckler, Andrew J., et al.
(författare)
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Patient-specific biomechanical analysis of atherosclerotic plaques enabled by histologically validated tissue characterization from computed tomography angiography : A case study
- 2022
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Ingår i: Journal of The Mechanical Behavior of Biomedical Materials. - : Elsevier BV. - 1751-6161 .- 1878-0180. ; 134
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Tidskriftsartikel (refereegranskat)abstract
- Background: Rupture of unstable atherosclerotic plaques with a large lipid-rich necrotic core and a thin fibrous cap cause myocardial infarction and stroke. Yet it has not been possible to assess this for individual patients. Clinical guidelines still rely on use of luminal narrowing, a poor indicator but one that persists for lack of effective means to do better. We present a case study demonstrating the assessment of biomechanical indices pertaining to plaque rupture risk non-invasively for individual patients enabled by histologically validated tissue characterization. Methods: Routinely acquired clinical images of plaques were analyzed to characterize vascular wall tissues using software validated by histology (ElucidVivo, Elucid Bioimaging Inc.). Based on the tissue distribution, wall stress and strain were then calculated at spatial locations with varied fibrous cap thicknesses at diastolic, mean and systolic blood pressures. Results: The von Mises stress of 152 [131, 172] kPa and the equivalent strain of 0.10 [0.08, 0.12] were calculated where the fibrous cap thickness was smallest (560 mu m) (95% CI in brackets). The stress at this location was at a level predictive of plaque failure. Stress and strain at locations with larger cap thicknesses were calculated to be lower, demonstrating a clinically relevant range of risk levels. Conclusion: Patient specific tissue characterization can identify distributions of stress and strain in a clinically relevant range. This capability may be used to identify high-risk lesions and personalize treatment decisions for individual patients with cardiovascular disease and improve prevention of myocardial infarction and stroke.
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| 3. |
- Buckler, Andrew J., et al.
(författare)
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Virtual Transcriptomics Noninvasive Phenotyping of Atherosclerosis by Decoding Plaque Biology From Computed Tomography Angiography Imaging
- 2021
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Ovid Technologies (Wolters Kluwer Health). - 1079-5642 .- 1524-4636. ; 41:5, s. 1738-1750
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Therapeutic advancements in atherosclerotic cardiovascular disease have improved prevention of ischemic stroke and myocardial infarction, but diagnostic methods for atherosclerotic plaque phenotyping to aid individualized therapy are lacking. In this feasibility study, we aimed to elucidate plaque biology by decoding the molecular phenotype of plaques through analysis of computed-tomography angiography images, making a predictive model for plaque biology referred to as virtual transcriptomics. Approach and Results: We employed machine intelligence using paired computed-tomography angiography and transcriptomics from carotid endarterectomies of 40 patients undergoing stroke-preventive surgery for carotid stenosis. Computed tomography angiographies were analyzed with novel software for accurate characterization of plaque morphology and plaque transcriptomes obtained from microarrays, followed by mathematical modeling for prediction of molecular signatures. Four hundred fourteen coding and noncoding RNAs were robustly predicted using supervised models to estimate gene expression based on plaque morphology. Examples of predicted transcripts included ion transporters, cytokine receptors, and a number of microRNAs whereas pathway analyses demonstrated enrichment of several biological processes relevant for the pathophysiology of atherosclerosis and plaque instability. Finally, the ability of the models to predict plaque gene expression was demonstrated using computed tomography angiographies from 4 sequestered patients and comparisons with transcriptomes of corresponding lesions. Conclusions: The results of this pilot study show that atherosclerotic plaque phenotyping by image analysis of conventional computed-tomography angiography can elucidate the molecular signature of atherosclerotic lesions in a multiscale setting. The study holds promise for optimized personalized therapy in the prevention of myocardial infarction and ischemic stroke, which warrants further investigations in larger cohorts.
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| 4. |
- Chemaly, Melody, et al.
(författare)
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Biliverdin Reductase B Is a Plasma Biomarker for Intraplaque Hemorrhage and a Predictor of Ischemic Stroke in Patients with Symptomatic Carotid Atherosclerosis
- 2023
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Ingår i: Biomolecules. - : MDPI AG. - 2218-273X. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid atherosclerosis and functionally associated with IPH. Objective: We explored the biomarker potential of plasma BLVRB through (1) its correlation with IPH in carotid plaques assessed by magnetic resonance imaging (MRI), and with recurrent ischemic stroke, and (2) its use for monitoring pharmacotherapy targeting IPH in a preclinical setting. Methods: Plasma BLVRB levels were measured in patients with symptomatic carotid atherosclerosis from the PARISK study (n = 177, 5 year follow-up) with and without IPH as indicated by MRI. Plasma BLVRB levels were also measured in a mouse vein graft model of IPH at baseline and following antiangiogenic therapy targeting vascular endothelial growth factor receptor 2 (VEGFR-2). Results: Plasma BLVRB levels were significantly higher in patients with IPH (737.32 & PLUSMN; 693.21 vs. 520.94 & PLUSMN; 499.43 mean fluorescent intensity (MFI), p = 0.033), but had no association with baseline clinical and biological parameters. Plasma BLVRB levels were also significantly higher in patients who developed recurrent ischemic stroke (1099.34 & PLUSMN; 928.49 vs. 582.07 & PLUSMN; 545.34 MFI, HR = 1.600, CI [1.092-2.344]; p = 0.016). Plasma BLVRB levels were significantly reduced following prevention of IPH by anti-VEGFR-2 therapy in mouse vein grafts (1189 & PLUSMN; 258.73 vs. 1752 & PLUSMN; 366.84 MFI; p = 0.004). Conclusions: Plasma BLVRB was associated with IPH and increased risk of recurrent ischemic stroke in patients with symptomatic low- to moderate-grade carotid stenosis, indicating the capacity to monitor the efficacy of IPH-preventive pharmacotherapy in an animal model. Together, these results suggest the utility of plasma BLVRB as a biomarker for atherosclerotic plaque instability.
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| 5. |
- Forteza, Maria J., et al.
(författare)
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Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk
- 2023
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Ingår i: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 119:7, s. 1524-1536
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies have revealed a close connection between cellular metabolism and the chronic inflammatory process of atherosclerosis. While the link between systemic metabolism and atherosclerosis is well established, the implications of altered metabolism in the artery wall are less understood. Pyruvate dehydrogenase kinase (PDK)-dependent inhibition of pyruvate dehydrogenase (PDH) has been identified as a major metabolic step regulating inflammation. Whether the PDK/PDH axis plays a role in vascular inflammation and atherosclerotic cardiovascular disease remains unclear. Methods and results Gene profiling of human atherosclerotic plaques revealed a strong correlation between PDK1 and PDK4 transcript levels and the expression of pro-inflammatory and destabilizing genes. Remarkably, the PDK1 and PDK4 expression correlated with a more vulnerable plaque phenotype, and PDK1 expression was found to predict future major adverse cardiovascular events. Using the small-molecule PDK inhibitor dichloroacetate (DCA) that restores arterial PDH activity, we demonstrated that the PDK/PDH axis is a major immunometabolic pathway, regulating immune cell polarization, plaque development, and fibrous cap formation in Apoe−/− mice. Surprisingly, we discovered that DCA regulates succinate release and mitigates its GPR91-dependent signals promoting NLRP3 inflammasome activation and IL-1β secretion by macrophages in the plaque. Conclusions We have demonstrated for the first time that the PDK/PDH axis is associated with vascular inflammation in humans and particularly that the PDK1 isozyme is associated with more severe disease and could predict secondary cardiovascular events. Moreover, we demonstrate that targeting the PDK/PDH axis with DCA skews the immune system, inhibits vascular inflammation and atherogenesis, and promotes plaque stability features in Apoe−/− mice. These results point toward a promising treatment to combat atherosclerosis.
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| 6. |
- Gasser, T. Christian, et al.
(författare)
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The interaction of biochemical, biomechanical, and clinical factors of coronary disease
- 2021
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Ingår i: Biomechanics of Coronary Atherosclerotic Plaque. - : Elsevier BV. ; , s. 171-190
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Coronary heart disease is a major and global health care challenge, and its biomechanical analysis has been shown to be a useful complement in answering related clinical questions. Compelling evidence has been accumulated showing that two primary biomechanical factors predispose to the disease: low or oscillating wall shear stress and high wall mechanical stress (or strain) of plaque tissue components. While the level of sophistication with which vascular biomechanical analysis can be made has increased dramatically, the utility of biomechanical models in clinical practice remains very limited and their capability is by far not fully exploited. This chapter aims at reviewing the principles of the biomechanical analysis of coronary arteries in relation to the interplay of biomechanical, biochemical, and clinical factors. Techniques, methods, and modeling assumptions are discussed in relation to their clinical relevance, and thus toward the feasibility of translating research results and developing new treatment techniques and diagnostic tools.
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| 7. |
- Hedin, Ulf, et al.
(författare)
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Resolving the biological paradox of aneurysm formation in children with tuberous sclerosis complex
- 2021
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Ingår i: JVS-Vascular Science. - : Elsevier BV. - 2666-3503. ; 2, s. 72-78
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Tidskriftsartikel (refereegranskat)abstract
- Aortic aneurysms are rare manifestations in children with tuberous sclerosis complex (TSC) with life threating implications. Although an association between TSC, aortic and other aneurysms has been recognized, mechanistic insights explaining the pathophysiology behind aneurysm development and genetic aberrations in TSC have so far been lacking. Here, we summarize existing knowledge on aneurysms in TSC and present a case of a 2-year-old boy with an infrarenal aortic aneurysm, successfully treated with open aortic reconstruction. Histologic examination of the excised aneurysm wall showed distortion of vessel wall structure with loss of elastin and a pathologic accumulation of smooth muscle cells. Until now, these pathologic features have puzzled researchers as proliferating smooth muscle cells would rather be expected to preserve vessel wall integrity. Recent reports exploring the biological consequences of the dysregulated intracellular signaling pathways in patients with TSC provide plausible explanations to this paradox, which may support the development of future therapeutic strategies.
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| 8. |
- Lundstrom, Ulrika Hahn, et al.
(författare)
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Surgical versus endovascular intervention for vascular access thrombosis : a nationwide observational cohort study
- 2022
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Ingår i: Nephrology, Dialysis and Transplantation. - : Oxford University Press. - 0931-0509 .- 1460-2385. ; 37:9, s. 1742-1750
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Tidskriftsartikel (refereegranskat)abstract
- Background There is no consensus whether an arteriovenous (AV) access thrombosis is best treated by surgical or endovascular intervention. We compared the influence of surgical versus endovascular intervention for AV access thrombosis on access survival using real-life data from a national access registry. Methods We included patients from the Swedish Renal Access Registry (SRR-Access) with a working AV access undergoing surgical or endovascular intervention for their first thrombosis between 2008 and 2020. The primary outcome was the risk of access abandonment (secondary patency at 30, 60, 90 and 365 days). Secondary outcomes were time to next intervention and 30-day mortality. Access characteristics were obtained from the SRR-Access and patient characteristics were collected from the Swedish Renal Registry. Outcomes were assessed with multivariable logistic regression and Cox proportional hazards regression models adjusted for demographics, clinical and access-related variables. Results A total of 904 patients with AV access thrombosis (54% arteriovenous fistula, 35% upper arm access) were included, with a mean age of 62 years, 60% were women, 75% had hypertension and 33% had diabetes. Secondary patency was superior after endovascular intervention versus surgical (85% versus 77% at 30 days and 76% versus 69% at 90 days). The adjusted odds of access abandonment within 90 days and 1 year were higher in the surgical thrombectomy group {odds ratio (OR) 1.44 [95% confidence interval (CI) 1.05-1.97] and OR 1.25 (0.94-1.66), respectively}. Results were consistent in the long-term analysis. There was no significant difference in time to next intervention or mortality, and results were consistent within subgroups. Conclusions Endovascular intervention was associated with a small short- and long-term benefit as compared with open surgery in haemodialysis patients with AV access thrombosis.
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| 9. |
- Paramel Varghese, Geena, 1985-, et al.
(författare)
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Expression of CARD8 in human atherosclerosis and its regulation of inflammatory proteins in human endothelial cells
- 2020
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- The Caspase activation and recruitment domain 8 (CARD8) protein is a component of innate immunity and overexpression of CARD8 mRNA was previously identified in atherosclerosis. However, very little is known about the regulation of CARD8 in endothelial cells and atherosclerosis. The aim of this study was to investigate CARD8 in the regulation of cytokine and chemokine expression in endothelial cells. Sections of human atherosclerotic lesions and non-atherosclerotic arteries were immunostained for CARD8 protein. Expression of CARD8 was correlated to mediators of inflammation in atherosclerotic lesions using Biobank of Karolinska Endarterectomies microarray data. The CARD8 mRNA was knocked-down in human umbilical vein endothelial cells (HUVECs) in vitro, followed by quantitative RT-PCR analysis and OLINK Proteomics. Endothelial and smooth muscle cells in arterial tissue expressed CARD8 and CARD8 correlated with vWF, CD163 and the expression of inflammatory genes, such as CXCL1, CXCL6 and PDGF-A in plaque. Knock-down of CARD8 in HUVECs significantly altered proteins involved in inflammatory response, such as CXCL1, CXCL6, PDGF-A, MCP-1 and IL-6. The present study suggest that CARD8 regulate the expression of cytokines and chemokines in endothelial cells and atherosclerotic lesions, suggesting that CARD8 plays a significant role in endothelial activation.
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| 10. |
- Röhl, Samuel, et al.
(författare)
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Transcriptomic profiling of experimental arterial injury reveals new mechanisms and temporal dynamics in vascular healing response
- 2020
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Ingår i: JVS-Vascular Science. - : Elsevier BV. - 2666-3503. ; 315, s. E14-E14
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Endovascular interventions cause arterial injury and induce a healing response to restore vessel wall homeostasis. Complications of defective or excessive healing are common and result in increased morbidity and repeated interventions. Experimental models of intimal hyperplasia are vital for understanding the vascular healing mechanisms and resolving the clinical problems of restenosis, vein graft stenosis, and dialysis access failure. Our aim was to systematically investigate the transcriptional, histologic, and systemic reaction to vascular injury during a prolonged time. Methods: Balloon injury of the left common carotid artery was performed in male rats. Animals (n = 69) were euthanized before or after injury, either directly or after 2 hours, 20 hours, 2 days, 5 days, 2 weeks, 6 weeks, and 12 weeks. Both injured and contralateral arteries were subjected to microarray profiling, followed by bioinformatic exploration, histologic characterization of the biopsy specimens, and plasma lipid analyses. Results: Immune activation and coagulation were key mechanisms in the early response, followed by cytokine release, tissue remodeling, and smooth muscle cell modulation several days after injury, with reacquisition of contractile features in later phases. Novel pathways related to clonal expansion, inflammatory transformation, and chondro-osteogenic differentiation were identified and immunolocalized to neointimal smooth muscle cells. Analysis of uninjured arteries revealed a systemic component of the reaction after local injury, underlined by altered endothelial signaling, changes in overall tissue bioenergy metabolism, and plasma high-density lipoprotein levels. Conclusions: We demonstrate that vascular injury induces dynamic transcriptional landscape and metabolic changes identifiable as early, intermediate, and late response phases, reaching homeostasis after several weeks. This study provides a temporal “roadmap” of vascular healing as a publicly available resource for the research community.
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