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  • 1
    Online Resource
    Online Resource
    Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 27 ( 2020-07-07), p. 15818-15826
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 27 ( 2020-07-07), p. 15818-15826
    Abstract: Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of “dedifferentiated” vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the mature SMC can give rise to a hyperproliferative cell which appears to promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsonin-sensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don’t eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2006348117
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 2
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    Longitudinal In Vivo Monitoring of Atheroprogression in Hypercholesterolemic Mice Using Photoacoustic Imaging
    Georg Thieme Verlag KG ; 2023
    In:  Thrombosis and Haemostasis Vol. 123, No. 05 ( 2023-05), p. 545-554
    Details
    In: Thrombosis and Haemostasis, Georg Thieme Verlag KG, Vol. 123, No. 05 ( 2023-05), p. 545-554
    Abstract: Background and Aim The ability to recognize and monitor atherosclerotic lesion development using noninvasive imaging is crucial in preventive cardiology. The aim of the present study was to establish a protocol for longitudinal monitoring of plaque lipid, collagen, and macrophage burden as well as of endothelial permeability. Methods and Results Photoacoustic signals derived from endogenous or exogenous dyes assessed in vivo, in plaques of albino Apoe −/− mice, correlated with lesion characteristics obtained after histomorphometric and immunofluorescence analyses, thus supporting the validity of our protocol. Using models of atheroprogression and regression, we could apply our imaging protocol to the longitudinal observation of atherosclerotic lesion characteristics in mice. Conclusions The present study shows an innovative approach to assess arterial inflammation in a non-invasive fashion, applicable to longitudinal analyses of changes of atherosclerotic lesion composition. Such approach could prove important in the preclinical testing of therapeutic interventions in mice carrying pre-established lesions.
    Type of Medium: Online Resource
    ISSN: 0340-6245 , 2567-689X
    URL: Article
    DOI: 10.1055/a-2005-8784
    Language: English
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2023
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  • 3
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    Argatroban and bivalirudin compared to unfractionated heparin in preventing thrombus formation on mechanical heart valves : Results of an in-vitro study
    Georg Thieme Verlag KG ; 2009
    In:  Thrombosis and Haemostasis Vol. 101, No. 06 ( 2009), p. 1163-1169
    Details
    In: Thrombosis and Haemostasis, Georg Thieme Verlag KG, Vol. 101, No. 06 ( 2009), p. 1163-1169
    Abstract: Prevention of valve thrombosis in patients after prosthetic mechanical heart valve replacement and heparin-induced thrombocytopenia (HIT) is still an open issue. The aim of the present in-vitro study was to investigate the efficacy of argatroban and bivalirudin in comparison to unfractionated heparin (UFH) in preventing thrombus formation on mechanical heart valves. Blood (230 ml) from healthy young male volunteers was anticoagulated either by UFH, argatroban bolus, argatroban bolus plus continuous infusion, bivalirudin bolus, or bivalirudin bolus plus continuous infusion. Valve prostheses were placed in a newly developed in-vitro thrombosis tester and exposed to the anticoagulated blood samples. To quantify the thrombi, electron microscopy was performed, and each valve was weighed before and after the experiment. Mean thrombus weight in group 1 (UFH) was 117 + 93 mg, in group 2 (argatroban bolus) 722 + 428 mg, in group 3 (bivalirudin bolus) 758 + 323 mg, in group 4 (argatroban bolus plus continuous infusion) 162 + 98 mg, and in group 5 (bivalirudin bolus plus continuous infusion) 166 + 141 mg (p-value 〈 0.001). Electron microscopy showed increased rates of thrombus formation in groups 2 and 3. Argatroban and bivalirudin were as effective as UFH in preventing thrombus formation on valve prostheses in our in-vitro investigation when they were administered continuously. We hypothesise that continuous infusion of argatroban or bivalirudin are optimal treatment options for patients with HIT after mechanical heart valve replacement for adapting oral to parenteral anticoagulation or vice versa.
    Type of Medium: Online Resource
    ISSN: 0340-6245 , 2567-689X
    URL: Article
    DOI: 10.1160/TH08-09-0571
    Language: English
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2009
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  • 4
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    The direct thrombin inhibitor argatroban effectively prevents cardiac catheter thrombosis in vitro
    Georg Thieme Verlag KG ; 2010
    In:  Thrombosis and Haemostasis Vol. 103, No. 04 ( 2010), p. 808-814
    Details
    In: Thrombosis and Haemostasis, Georg Thieme Verlag KG, Vol. 103, No. 04 ( 2010), p. 808-814
    Abstract: The direct thrombin inhibitor argatroban offers some significant advantages over unfractionated heparin (UFH) and is recommended as an alternative anticoagulant during percutaneous coronary interventions (PCI). The impact of argatroban on cardiac catheter thrombosis – a severe potential complication of PCI – has not been systematically studied yet. The aim of the present study was to test in vitro the hypothesis that argatroban is equivalent to the more established anticoagulants UFH and enoxaparin in preventing catheter thrombus formation. Blood pretreated with the anticoagulants of interest was continuously circulated through a guiding catheter by using a roller pump for a maximum experimental period of 60 minutes. In an alternate model, coagulation was mechanically induced by a magnetic stirrer. Coagulation parameters, overall thrombus weight and electron microscopic features (deposits of platelets and fibrin on the catheter surface) were quantified as endpoints. Argatroban (administered as bolus or continuous in-fusion), UFH (bolus), and enoxaparin (bolus) significantly reduced catheter thrombus formation compared to untreated controls. Here, neither overall thrombus weight nor platelet/fibrin deposition was different among the specific anticoagulants. Declining ACT (activated clotting time) levels – which were found in the argatroban bolus group – could be prevented by continuous infusion. In magnetic stirrer-induced coagulation, thrombus weight was lower following bolus treatment with UFH and enoxaparin compared to argatroban. These data suggest that the potential for argatroban in preventing catheter thrombosis is comparable to that of UFH and enoxaparin. However, the anticoagula-tory efficacy varied, depending on the model of coagulation activation, which demonstrates the necessity for specific testing.
    Type of Medium: Online Resource
    ISSN: 0340-6245 , 2567-689X
    URL: Article
    DOI: 10.1160/TH09-07-0456
    Language: English
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2010
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  • 5
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    Endotoxinemia Accelerates Atherosclerosis Through Electrostatic Charge–Mediated Monocyte Adhesion
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Circulation Vol. 143, No. 3 ( 2021-01-19), p. 254-266
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 143, No. 3 ( 2021-01-19), p. 254-266
    Abstract: Acute infection is a well-established risk factor of cardiovascular inflammation increasing the risk for a cardiovascular complication within the first weeks after infection. However, the nature of the processes underlying such aggravation remains unclear. Lipopolysaccharide derived from Gram-negative bacteria is a potent activator of circulating immune cells including neutrophils, which foster inflammation through discharge of neutrophil extracellular traps (NETs). Here, we use a model of endotoxinemia to link acute infection and subsequent neutrophil activation with acceleration of vascular inflammation Methods: Acute infection was mimicked by injection of a single dose of lipopolysaccharide into hypercholesterolemic mice. Atherosclerosis burden was studied by histomorphometric analysis of the aortic root. Arterial myeloid cell adhesion was quantified by intravital microscopy. Results: Lipopolysaccharide treatment rapidly enhanced atherosclerotic lesion size by expansion of the lesional myeloid cell accumulation. Lipopolysaccharide treatment led to the deposition of NETs along the arterial lumen, and inhibition of NET release annulled lesion expansion during endotoxinemia, thus suggesting that NETs regulate myeloid cell recruitment. To study the mechanism of monocyte adhesion to NETs, we used in vitro adhesion assays and biophysical approaches. In these experiments, NET-resident histone H2a attracted monocytes in a receptor-independent, surface charge–dependent fashion. Therapeutic neutralization of histone H2a by antibodies or by in silico designed cyclic peptides enables us to reduce luminal monocyte adhesion and lesion expansion during endotoxinemia. Conclusions: Our study shows that NET-associated histone H2a mediates charge-dependent monocyte adhesion to NETs and accelerates atherosclerosis during endotoxinemia.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.120.046677
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1466401-X
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  • 6
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    Proefferocytic Therapy Promotes Transforming Growth Factor-β Signaling and Prevents Aneurysm Formation
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Circulation Vol. 137, No. 7 ( 2018-02-13), p. 750-753
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 137, No. 7 ( 2018-02-13), p. 750-753
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.117.030389
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 1466401-X
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  • 7
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    INKILN is a Novel Long Noncoding RNA Promoting Vascular Smooth Muscle Inflammation via Scaffolding MKL1 and USP10
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Circulation Vol. 148, No. 1 ( 2023-07-04), p. 47-67
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 148, No. 1 ( 2023-07-04), p. 47-67
    Abstract: Activation of vascular smooth muscle cell (VSMC) inflammation is vital to initiate vascular disease. The role of human-specific long noncoding RNAs in VSMC inflammation is poorly understood. Methods: Bulk RNA sequencing in differentiated human VSMCs revealed a novel human-specific long noncoding RNA called inflammatory MKL1 (megakaryoblastic leukemia 1) interacting long noncoding RNA ( INKILN ). INKILN expression was assessed in multiple in vitro and ex vivo models of VSMC phenotypic modulation as well as human atherosclerosis and abdominal aortic aneurysm. The transcriptional regulation of INKILN was verified through luciferase reporter and chromatin immunoprecipitation assays. Loss-of-function and gain-of-function studies and multiple RNA–protein and protein–protein interaction assays were used to uncover a mechanistic role of INKILN in the VSMC proinflammatory gene program. Bacterial artificial chromosome transgenic mice were used to study INKILN expression and function in ligation injury–induced neointimal formation. Results: INKILN expression is downregulated in contractile VSMCs and induced in human atherosclerosis and abdominal aortic aneurysm. INKILN is transcriptionally activated by the p65 pathway, partially through a predicted NF-κB (nuclear factor kappa B) site within its proximal promoter. INKILN activates proinflammatory gene expression in cultured human VSMCs and ex vivo cultured vessels. INKILN physically interacts with and stabilizes MKL1, a key activator of VSMC inflammation through the p65/NF-κB pathway. INKILN depletion blocks interleukin-1β–induced nuclear localization of both p65 and MKL1. Knockdown of INKILN abolishes the physical interaction between p65 and MKL1 and the luciferase activity of an NF-κB reporter. Furthermore, INKILN knockdown enhances MKL1 ubiquitination through reduced physical interaction with the deubiquitinating enzyme USP10 (ubiquitin-specific peptidase 10). INKILN is induced in injured carotid arteries and exacerbates ligation injury–induced neointimal formation in bacterial artificial chromosome transgenic mice. Conclusions: These findings elucidate an important pathway of VSMC inflammation involving an INKILN /MKL1/USP10 regulatory axis. Human bacterial artificial chromosome transgenic mice offer a novel and physiologically relevant approach for investigating human-specific long noncoding RNAs under vascular disease conditions.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.123.063760
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 1466401-X
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  • 8
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    Non-coding RNAs in aneurysmal aortopathy
    Elsevier BV ; 2019
    In:  Vascular Pharmacology Vol. 114 ( 2019-03), p. 110-121
    Details
    In: Vascular Pharmacology, Elsevier BV, Vol. 114 ( 2019-03), p. 110-121
    Type of Medium: Online Resource
    ISSN: 1537-1891
    URL: Article
    DOI: 10.1016/j.vph.2018.06.008
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 2089264-0
    SSG: 15,3
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  • 9
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    Abstract 301: Angiotensin II-induced Aortic Stiffening is Associated With Upregulation of Mir-21 And Downregulation of Mir-29b
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 33, No. suppl_1 ( 2013-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 33, No. suppl_1 ( 2013-05)
    Abstract: Arterial stiffening is associated with aging, as well as numerous diseases such as hypertension, congestive heart failure, diabetes mellitus and renal failure, and has been identified as an independent risk factor for cardiovascular disease. Consequently there is a growing interest in the mechanisms that govern the process of arterial remodeling. Recently, small noncoding RNAs, termed microRNAs (miRs), have emerged as powerful cellular regulators involved in disease and tissue remodeling. More specifically, miR-29b downregulation as well as miR-21 upregulation have been identified as pro-fibrotic mechanisms in various cardiovascular disease models. This study investigated the role of miR-21 and miR-29b in a mouse model of AngII-induced arterial remodeling. Materials and methods Angiotensin II (AngII) (1000ng/kg/min) was infused via osmotic pumps in 10-week-old apoE-/- male mice (C57BL/6J background) for 7 days. Subsequently, arterial stiffness was determined in vivo using ultrasound-based measurements. Abdominal aortas were harvested and expression of various collagen isoforms (Col1a1, Col3a1, Col5a1) known to be crucial determinants of arterial remodeling/stiffening was quantified via qRT-PCR. We also measured expression levels of miR-21 and miR-29b. Results AngII stimulation resulted in an increased aortic stiffness paralleled by a marked pro-fibrotic response as evidenced by significant increases in Col1a1, Col3a1, and Col5a1 in the infrarenal aorta compared to baseline levels (p 〈 0.05). This increase was accompanied by significant downregulation of miR-29b, and upregulation of miR-21 (p 〈 0.05). Conclusion The pro-fibrotic response in AngII-mediated arterial remodeling is associated with an increase in miR-21 and a decrease in miR-29b. Modulation of miR-21 and miR-29b have both been successful in altering fibrotic mechanisms in various cardiovascular diseases. These data suggest they may also be potential targets in the treatment of hypertensive vascular remodeling/arterial stiffening.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.33.suppl_1.A301
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 1494427-3
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  • 10
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    Abstract 556: Targeted Screening Reveals microRNAs of Therapeutic Interest in Radiotherapy-Induced Vascular Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 35, No. suppl_1 ( 2015-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. suppl_1 ( 2015-05)
    Abstract: Radiotherapy is an established therapeutic method in many different cancer types. The success of modern cancer treatment raises a new problem, namely radiotherapy-induced vascular disease (vRTx) or vasculopathy, which typically emerges in irradiated areas of the heart, neck and brain and manifests itself as coronary disease, heart failure or carotid stenosis. A chronic inflammatory response likely underlies vRTx. Like in atherosclerosis, complex biological processes such as vascular cell proliferation, remodeling, oxidative stress, and tumor growth factor β (TGF-β)-regulated nuclear factor kappa B (NF-κB) activation are involved. These processes are tightly regulated by a multitude of factors, which separately are difficult to influence. A set of miRNAs known to orchestrate these processes in other disease contexts likely also play a role in vRTx, and might be modifiable in order to treat or prevent RTx-induced vascular disease. We selected miR-29b, miR-125a, miR-126, miR-143, miR-145, miR-146a, miR-155, miR-221, miR-222, and miR-503 and determined their potential contribution to vRTx. Utilizing unique biobank material from microvascular free tissue transfer reconstructions, where irradiated (R) vascular tissue (branches from external carotid arteries and internal jugular veins) can be compared with non-irradiated control tissue (NR) within the same patient (n=10), we could precisely determine which miRNAs become deregulated after irradiation. Currently we are using a mouse model of local irradiation for further analysis and assessment of miRNA modulation effects. Apoe -/- mice are irradiated in the mediastinal area; control littermates were sham irradiated. We checked the expression of the 10 pre-selected miRNAs in R vs. NR vascular tissue (ascending and thoracic aorta). Of the 10 miRNAs, three (miR-29b up-; miR-143, miR-145 downregulated) were significantly differentially regulated between R and NR human arteries. miR-146a trended upward, but not significantly. Ongoing studies are aimed at histological analysis of mouse R vs. NR tissue, functional modulation of deregulated miRNAs in vivo to assess vRTx outcome, and in vitro assessment of miRNA expression differences in different human vascular cell lines exposed to radiation.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.35.suppl_1.556
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1494427-3
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