Publications by authors named "Alma Zernecke"

147 Publications

Simultaneous measurements of 3D wall shear stress and pulse wave velocity in the murine aortic arch.

J Cardiovasc Magn Reson 2021 03 18;23(1):34. Epub 2021 Mar 18.

Experimental Physiks V, University of Würzburg, Am Hubland, 97074, Würzburg, Germany.

Purpose: Wall shear stress (WSS) and pulse wave velocity (PWV) are important parameters to characterize blood flow in the vessel wall. Their quantification with flow-sensitive phase-contrast (PC) cardiovascular magnetic resonance (CMR), however, is time-consuming. Furthermore, the measurement of WSS requires high spatial resolution, whereas high temporal resolution is necessary for PWV measurements. For these reasons, PWV and WSS are challenging to measure in one CMR session, making it difficult to directly compare these parameters. By using a retrospective approach with a flexible reconstruction framework, we here aimed to simultaneously assess both PWV and WSS in the murine aortic arch from the same 4D flow measurement.

Methods: Flow was measured in the aortic arch of 18-week-old wildtype (n = 5) and ApoE mice (n = 5) with a self-navigated radial 4D-PC-CMR sequence. Retrospective data analysis was used to reconstruct the same dataset either at low spatial and high temporal resolution (PWV analysis) or high spatial and low temporal resolution (WSS analysis). To assess WSS, the aortic lumen was labeled by semi-automatically segmenting the reconstruction with high spatial resolution. WSS was determined from the spatial velocity gradients at the lumen surface. For calculation of the PWV, segmentation data was interpolated along the temporal dimension. Subsequently, PWV was quantified from the through-plane flow data using the multiple-points transit-time method. Reconstructions with varying frame rates and spatial resolutions were performed to investigate the influence of spatiotemporal resolution on the PWV and WSS quantification.

Results: 4D flow measurements were conducted in an acquisition time of only 35 min. Increased peak flow and peak WSS values and lower errors in PWV estimation were observed in the reconstructions with high temporal resolution. Aortic PWV was significantly increased in ApoE mice compared to the control group (1.7 ± 0.2 versus 2.6 ± 0.2 m/s, p < 0.001). Mean WSS magnitude values averaged over the aortic arch were (1.17 ± 0.07) N/m in wildtype mice and (1.27 ± 0.10) N/m in ApoE mice.

Conclusion: The post processing algorithm using the flexible reconstruction framework developed in this study permitted quantification of global PWV and 3D-WSS in a single acquisition. The possibility to assess both parameters in only 35 min will markedly improve the analyses and information content of in vivo measurements.
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http://dx.doi.org/10.1186/s12968-021-00725-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972216PMC
March 2021

Evaluation of Plaque Characteristics and Inflammation Using Magnetic Resonance Imaging.

Biomedicines 2021 Feb 12;9(2). Epub 2021 Feb 12.

Institute of Experimental Biomedicine, University Hospital Würzburg, 97080 Würzburg, Germany.

Atherosclerosis is an inflammatory disease of large and medium-sized arteries, characterized by the growth of atherosclerotic lesions (plaques). These plaques often develop at inner curvatures of arteries, branchpoints, and bifurcations, where the endothelial wall shear stress is low and oscillatory. In conjunction with other processes such as lipid deposition, biomechanical factors lead to local vascular inflammation and plaque growth. There is also evidence that low and oscillatory shear stress contribute to arterial remodeling, entailing a loss in arterial elasticity and, therefore, an increased pulse-wave velocity. Although altered shear stress profiles, elasticity and inflammation are closely intertwined and critical for plaque growth, preclinical and clinical investigations for atherosclerosis mostly focus on the investigation of one of these parameters only due to the experimental limitations. However, cardiovascular magnetic resonance imaging (MRI) has been demonstrated to be a potent tool which can be used to provide insights into a large range of biological parameters in one experimental session. It enables the evaluation of the dynamic process of atherosclerotic lesion formation without the need for harmful radiation. Flow-sensitive MRI provides the assessment of hemodynamic parameters such as wall shear stress and pulse wave velocity which may replace invasive and radiation-based techniques for imaging of the vascular function and the characterization of early plaque development. In combination with inflammation imaging, the analyses and correlations of these parameters could not only significantly advance basic preclinical investigations of atherosclerotic lesion formation and progression, but also the diagnostic clinical evaluation for early identification of high-risk plaques, which are prone to rupture. In this review, we summarize the key applications of magnetic resonance imaging for the evaluation of plaque characteristics through flow sensitive and morphological measurements. The simultaneous measurements of functional and structural parameters will further preclinical research on atherosclerosis and has the potential to fundamentally improve the detection of inflammation and vulnerable plaques in patients.
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http://dx.doi.org/10.3390/biomedicines9020185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917750PMC
February 2021

Immuno-metabolic interfaces in cardiac disease and failure.

Cardiovasc Res 2021 Feb 4. Epub 2021 Feb 4.

Department of Translational Research, Comprehensive Heart Failure Center (CHFC), University Hospital Würzburg, Germany.

The interplay between the cardiovascular system, metabolism, and inflammation plays a central role in the pathophysiology of a wide spectrum of cardiovascular diseases, including heart failure. Here, we provide an overview of the fundamental aspects of the interrelation between inflammation and metabolism, ranging from the role of metabolism in immune cell function to the processes how inflammation modulates systemic and cardiac metabolism. Furthermore, we discuss how disruption of this immuno-metabolic interface is involved in the development and progression of cardiovascular disease, with a special focus on heart failure. Finally, we present new technologies and therapeutic approaches that have recently emerged and hold promise for the future of cardiovascular medicine.
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http://dx.doi.org/10.1093/cvr/cvab036DOI Listing
February 2021

CD8 T Cells in Atherosclerosis.

Cells 2020 12 29;10(1). Epub 2020 Dec 29.

Institute of Experimental Biomedicine, University Hospital Würzburg, 97080 Würzburg, Germany.

Atherosclerotic lesions are populated by cells of the innate and adaptive immune system, including CD8 T cells. The CD8 T cell infiltrate has recently been characterized in mouse and human atherosclerosis and revealed activated, cytotoxic, and possibly dysfunctional and exhausted cell phenotypes. In mouse models of atherosclerosis, antibody-mediated depletion of CD8 T cells ameliorates atherosclerosis. CD8 T cells control monopoiesis and macrophage accumulation in early atherosclerosis. In addition, CD8 T cells exert cytotoxic functions in atherosclerotic plaques and contribute to macrophage cell death and necrotic core formation. CD8 T cell activation may be antigen-specific, and epitopes of atherosclerosis-relevant antigens may be targets of CD8 T cells and their cytotoxic activity. CD8 T cell functions are tightly controlled by costimulatory and coinhibitory immune checkpoints. Subsets of regulatory CD25CD8 T cells with immunosuppressive functions can inhibit atherosclerosis. Importantly, local cytotoxic CD8 T cell responses may trigger endothelial damage and plaque erosion in acute coronary syndromes. Understanding the complex role of CD8 T cells in atherosclerosis may pave the way for defining novel treatment approaches in atherosclerosis. In this review article, we discuss these aspects, highlighting the emerging and critical role of CD8 T cells in atherosclerosis.
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http://dx.doi.org/10.3390/cells10010037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823404PMC
December 2020

Dynamics of Cardiac Neutrophil Diversity in Murine Myocardial Infarction.

Circ Res 2020 10 19;127(9):e232-e249. Epub 2020 Aug 19.

Comprehensive Heart Failure Center Wuerzburg (G.R., L.K., A.-P.A.-L., V.A.N., D.J.J.S., C.C.), University Hospital Wuerzburg, Germany.

Rationale: After myocardial infarction, neutrophils rapidly and massively infiltrate the heart, where they promote both tissue healing and damage.

Objective: To characterize the dynamics of circulating and cardiac neutrophil diversity after infarction.

Methods And Results: We employed single-cell transcriptomics combined with cell surface epitope detection by sequencing to investigate temporal neutrophil diversity in the blood and heart after murine myocardial infarction. At day 1, 3, and 5 after infarction, cardiac Ly6G (lymphocyte antigen 6G) neutrophils could be delineated into 6 distinct clusters with specific time-dependent patterning and proportions. At day 1, neutrophils were characterized by a gene expression profile proximal to bone marrow neutrophils (, , ), and putative activity of transcriptional regulators involved in hypoxic response () and emergency granulopoiesis (). At 3 and 5 days, 2 major subsets of (enriched for eg, and ) and () neutrophils were found. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analysis in blood and heart revealed that while circulating neutrophils undergo a process of aging characterized by loss of surface CD62L and upregulation of , heart infiltrating neutrophils acquired a unique SiglecF signature. SiglecF neutrophils were absent from the bone marrow and spleen, indicating local acquisition of the SiglecF signature. Reducing the influx of blood neutrophils by anti-Ly6G treatment increased proportions of cardiac SiglecF neutrophils, suggesting accumulation of locally aged neutrophils. Computational analysis of ligand/receptor interactions revealed putative pathways mediating neutrophil to macrophage communication in the myocardium. Finally, SiglecF neutrophils were also found in atherosclerotic vessels, revealing that they arise across distinct contexts of cardiovascular inflammation.

Conclusions: Altogether, our data provide a time-resolved census of neutrophil diversity and gene expression dynamics in the mouse blood and ischemic heart at the single-cell level, and reveal a process of local tissue specification of neutrophils in the ischemic heart characterized by the acquisition of a SiglecF signature.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317200DOI Listing
October 2020

Meta-Analysis of Leukocyte Diversity in Atherosclerotic Mouse Aortas.

Circ Res 2020 07 16;127(3):402-426. Epub 2020 Jul 16.

La Jolla Institute for Immunology, CA (C.C.H., Y.G., H.Q.D., K.L.).

The diverse leukocyte infiltrate in atherosclerotic mouse aortas was recently analyzed in 9 single-cell RNA sequencing and 2 mass cytometry studies. In a comprehensive meta-analysis, we confirm 4 known macrophage subsets-resident, inflammatory, interferon-inducible cell, and Trem2 (triggering receptor expressed on myeloid cells-2) foamy macrophages-and identify a new macrophage subset resembling cavity macrophages. We also find that monocytes, neutrophils, dendritic cells, natural killer cells, innate lymphoid cells-2, and CD (cluster of differentiation)-8 T cells form prominent and separate immune cell populations in atherosclerotic aortas. Many CD4 T cells express IL (interleukin)-17 and the chemokine receptor CXCR (C-X-C chemokine receptor)-6. A small number of regulatory T cells and T helper 1 cells is also identified. Immature and naive T cells are present in both healthy and atherosclerotic aortas. Our meta-analysis overcomes limitations of individual studies that, because of their experimental approach, over- or underrepresent certain cell populations. Mass cytometry studies demonstrate that cell surface phenotype provides valuable information beyond the cell transcriptomes. The present analysis helps resolve some long-standing controversies in the field. First, Trem2 foamy macrophages are not proinflammatory but interferon-inducible cell and inflammatory macrophages are. Second, about half of all foam cells are smooth muscle cell-derived, retaining smooth muscle cell transcripts rather than transdifferentiating to macrophages. Third, , which had been considered specific for platelets and megakaryocytes, is also prominently expressed in the main population of resident vascular macrophages. Fourth, a new type of resident macrophage shares transcripts with cavity macrophages. Finally, the discovery of a prominent innate lymphoid cell-2 cluster links the single-cell RNA sequencing work to recent flow cytometry data suggesting a strong atheroprotective role of innate lymphoid cells-2. This resolves apparent discrepancies regarding the role of T helper 2 cells in atherosclerosis based on studies that predated the discovery of innate lymphoid cells-2 cells.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.316903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371244PMC
July 2020

Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects.

Nat Commun 2020 04 7;11(1):1733. Epub 2020 Apr 7.

Institute of Pharmacology and Toxicology, University of Würzburg, 97078, Würzburg, Germany.

Dysregulation of extracellular signal-regulated kinases (ERK1/2) is linked to several diseases including heart failure, genetic syndromes and cancer. Inhibition of ERK1/2, however, can cause severe cardiac side-effects, precluding its wide therapeutic application. ERK-autophosphorylation was identified to cause pathological cardiac hypertrophy. Here we report that interference with ERK-dimerization, a prerequisite for ERK-phosphorylation, minimizes cardiac hypertrophy without inducing cardiac adverse effects: an ERK-dimerization inhibitory peptide (EDI) prevents ERK-phosphorylation, nuclear ERK1/2-signaling and cardiomyocyte hypertrophy, protecting from pressure-overload-induced heart failure in mice whilst preserving ERK1/2-activity and cytosolic survival signaling. We also examine this alternative ERK1/2-targeting strategy in cancer: indeed, ERK-phosphorylation is strongly upregulated in cancer and EDI efficiently suppresses cancer cell proliferation without causing cardiotoxicity. This powerful cardio-safe strategy of interfering with ERK-dimerization thus combats pathological ERK1/2-signaling in heart and cancer, and may potentially expand therapeutic options for ERK1/2-related diseases, such as heart failure and genetic syndromes.
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http://dx.doi.org/10.1038/s41467-020-15505-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138859PMC
April 2020

Phosphorylation-Dependent Differences in CXCR4-LASP1-AKT1 Interaction between Breast Cancer and Chronic Myeloid Leukemia.

Cells 2020 02 14;9(2). Epub 2020 Feb 14.

Klinik für Innere Medizin II, Abteilung für Hämatologie und internistische Onkologie, Universitätsklinikum Jena, Am Klinikum 1, 07747 Jena, Germany.

The serine/threonine protein kinase AKT1 is a downstream target of the chemokine receptor 4 (CXCR4), and both proteins play a central role in the modulation of diverse cellular processes, including proliferation and cell survival. While in chronic myeloid leukemia (CML) the CXCR4 is downregulated, thereby promoting the mobilization of progenitor cells into blood, the receptor is highly expressed in breast cancer cells, favoring the migratory capacity of these cells. Recently, the LIM and SH3 domain protein 1 (LASP1) has been described as a novel CXCR4 binding partner and as a promoter of the PI3K/AKT pathway. In this study, we uncovered a direct binding of LASP1, phosphorylated at S146, to both CXCR4 and AKT1, as shown by immunoprecipitation assays, pull-down experiments, and immunohistochemistry data. In contrast, phosphorylation of LASP1 at Y171 abrogated these interactions, suggesting that both LASP1 phospho-forms interact. Finally, findings demonstrating different phosphorylation patterns of LASP1 in breast cancer and chronic myeloid leukemia may have implications for CXCR4 function and tyrosine kinase inhibitor treatment.
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http://dx.doi.org/10.3390/cells9020444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072741PMC
February 2020

Knockout of LASP1 in CXCR4 expressing CML cells promotes cell persistence, proliferation and TKI resistance.

J Cell Mol Med 2020 03 19;24(5):2942-2955. Epub 2020 Jan 19.

Abteilung für Hämatologie und internistische Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.

Chronic myeloid leukaemia (CML) is a clonal myeloproliferative stem cell disorder characterized by the constitutively active BCR-ABL tyrosine kinase. The LIM and SH3 domain protein 1 (LASP1) has recently been identified as a novel BCR-ABL substrate and is associated with proliferation, migration, tumorigenesis and chemoresistance in several cancers. Furthermore, LASP1 was shown to bind to the chemokine receptor 4 (CXCR4), thought to be involved in mechanisms of relapse. In order to identify potential LASP1-mediated pathways and related factors that may help to further eradicate minimal residual disease (MRD), the effect of LASP1 on processes involved in progression and maintenance of CML was investigated. The present data indicate that not only overexpression of CXCR4, but also knockout of LASP1 contributes to proliferation, reduced apoptosis and migration as well as increased adhesive potential of K562 CML cells. Furthermore, LASP1 depletion in K562 CML cells leads to decreased cytokine release and reduced NK cell-mediated cytotoxicity towards CML cells. Taken together, these results indicate that in CML, reduced levels of LASP1 alone and in combination with high CXCR4 expression may contribute to TKI resistance.
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http://dx.doi.org/10.1111/jcmm.14910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077607PMC
March 2020

Mass Spectrometry Imaging of atherosclerosis-affine Gadofluorine following Magnetic Resonance Imaging.

Sci Rep 2020 01 9;10(1):79. Epub 2020 Jan 9.

Department of Diagnostic and Interventional Radiology, School of Medicine & Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Molecular imaging of atherosclerosis by Magnetic Resonance Imaging (MRI) has been impaired by a lack of validation of the specific substrate responsible for the molecular imaging signal. We therefore aimed to investigate the additive value of mass spectrometry imaging (MSI) of atherosclerosis-affine Gadofluorine P for molecular MRI of atherosclerotic plaques. Atherosclerotic Ldlr mice were investigated by high-field MRI (7 T) at different time points following injection of atherosclerosis-affine Gadofluorine P as well as at different stages of atherosclerosis formation (4, 8, 16 and 20 weeks of HFD). At each imaging time point mice were immediately sacrificed after imaging and aortas were excised for mass spectrometry imaging: Matrix Assisted Laser Desorption Ionization (MALDI) Imaging and Laser Ablation - Inductively Coupled Plasma - Mass Spectrometry (LA-ICP-MS) imaging. Mass spectrometry imaging allowed to visualize the localization and measure the concentration of the MR imaging probe Gadofluorine P in plaque tissue ex vivo with high spatial resolution and thus adds novel and more target specific information to molecular MR imaging of atherosclerosis.
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http://dx.doi.org/10.1038/s41598-019-57075-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952459PMC
January 2020

Stabilization of Perivascular Mast Cells by Endothelial CNP (C-Type Natriuretic Peptide).

Arterioscler Thromb Vasc Biol 2020 03 2;40(3):682-696. Epub 2020 Jan 2.

From the Institute of Physiology, University of Würzburg, Germany (W.C., F.W., K.V., T.P., M.K.).

Objective: Activated perivascular mast cells (MCs) participate in different cardiovascular diseases. Many factors provoking MC degranulation have been described, while physiological counterregulators are barely known. Endothelial CNP (C-type natriuretic peptide) participates in the maintenance of vascular barrier integrity, but the target cells and mechanisms are unclear. Here, we studied whether MCs are regulated by CNP. Approach and Results: In cultured human and murine MCs, CNP activated its specific GC (guanylyl cyclase)-B receptor and cyclic GMP signaling. This enhanced cyclic GMP-dependent phosphorylation of the cytoskeleton-associated VASP (vasodilator-stimulated phosphoprotein) and inhibited ATP-evoked degranulation. To elucidate the relevance in vivo, mice with a floxed GC-B () gene were interbred with a line to generate mice lacking GC-B in connective tissue MCs (MC GC-B knockout). In anesthetized mice, acute ischemia-reperfusion of the cremaster muscle microcirculation provoked extensive MC degranulation and macromolecule extravasation. Superfusion of CNP markedly prevented MC activation and endothelial barrier disruption in control but not in MC GC-B knockout mice. Notably, already under resting conditions, such knockout mice had increased numbers of degranulated MCs in different tissues, together with elevated plasma chymase levels. After transient coronary occlusion, their myocardial areas at risk and with infarction were enlarged. Moreover, MC GC-B knockout mice showed augmented perivascular neutrophil infiltration and deep vein thrombosis in a model of inferior vena cava ligation.

Conclusions: CNP, via GC-B/cyclic GMP signaling, stabilizes resident perivascular MCs at baseline and prevents their excessive activation under pathological conditions. Thereby CNP contributes to the maintenance of vascular integrity in physiology and disease.
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http://dx.doi.org/10.1161/ATVBAHA.119.313702DOI Listing
March 2020

Non-activatable mutant of inhibitor of kappa B kinase α (IKKα) exerts vascular site-specific effects on atherosclerosis in Apoe-deficient mice.

Atherosclerosis 2020 01 2;292:23-30. Epub 2019 Nov 2.

Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Germany. Electronic address:

Background And Aims: IKKα is an important regulator of gene expression. As IKKα kinase inactivity in bone marrow-derived cells does not affect atherosclerosis, we here investigate the impact of a whole body-IKKα kinase inactivity on atherosclerosis.

Methods: Apolipoprotein E (Apoe)-deficient mice homozygous for an activation-resistant Ikkα-mutant (IkkαApoe) and IkkαApoe controls received a Western-type diet. Atherosclerotic lesion size and cellular content were analyzed using histology and immunofluorescence. Vascular protein expression and IKKα kinase activity were quantified by Luminex multiplex immuno-assay and ELISA.

Results: A vascular site-specific IKKα expression and kinase activation profile was revealed, with higher total IKKα protein levels in aortic root but increased IKKα phosphorylation, representing activated IKKα, in the aortic arch. This was associated with a vascular site-specific effect of Ikkα knock-in on atherosclerosis: in the aortic root, Ikkα knock-in decreased lesion size by 22.0 ± 7.7% (p < 0.01), reduced absolute lesional smooth muscle cell numbers and lowered pro-atherogenic MMP2. In contrast, Ikkα knock-in increased lesion size in the aortic arch by 43.7 ± 20.1% (p < 0.001), increased the abundance of lesional smooth muscle cells in brachiocephalic artery as main arch side branch and elevated MMP2. A similar profile was observed for MMP3. No effects were observed on necrotic core or collagen deposition in atherosclerotic lesions, nor on absolute lesional macrophage numbers.

Conclusions: A non-activatable IKKα kinase differentially affects atherosclerosis in aortic root vs. aortic arch/brachiocephalic artery, associated with a differential vascular IKKα expression and kinase activation profile as well as with a vascular site-dependent impact on lesional smooth muscle cell accumulation and protein expression profiles.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.10.023DOI Listing
January 2020

Fast self-navigated wall shear stress measurements in the murine aortic arch using radial 4D-phase contrast cardiovascular magnetic resonance at 17.6 T.

J Cardiovasc Magn Reson 2019 10 14;21(1):64. Epub 2019 Oct 14.

Experimental Physiks V, University of Würzburg, Am Hubland, 97074, Würzburg, Germany.

Purpose: 4D flow cardiovascular magnetic resonance (CMR) and the assessment of wall shear stress (WSS) are non-invasive tools to study cardiovascular risks in vivo. Major limitations of conventional triggered methods are the long measurement times needed for high-resolution data sets and the necessity of stable electrocardiographic (ECG) triggering. In this work an ECG-free retrospectively synchronized method is presented that enables accelerated high-resolution measurements of 4D flow and WSS in the aortic arch of mice.

Methods: 4D flow and WSS were measured in the aortic arch of 12-week-old wildtype C57BL/6 J mice (n = 7) with a radial 4D-phase-contrast (PC)-CMR sequence, which was validated in a flow phantom. Cardiac and respiratory motion signals were extracted from the radial CMR signal and were used for the reconstruction of 4D-flow data. Rigid motion correction and a first order B correction was used to improve the robustness of magnitude and velocity data. The aortic lumen was segmented semi-automatically. Temporally averaged and time-resolved WSS and oscillatory shear index (OSI) were calculated from the spatial velocity gradients at the lumen surface at 14 locations along the aortic arch. Reproducibility was tested in 3 animals and the influence of subsampling was investigated.

Results: Volume flow, cross-sectional areas, WSS and the OSI were determined in a measurement time of only 32 min. Longitudinal and circumferential WSS and radial stress were assessed at 14 analysis planes along the aortic arch. The average longitudinal, circumferential and radial stress values were 1.52 ± 0.29 N/m, 0.28 ± 0.24 N/m and - 0.21 ± 0.19 N/m, respectively. Good reproducibility of WSS values was observed.

Conclusion: This work presents a robust measurement of 4D flow and WSS in mice without the need of ECG trigger signals. The retrospective approach provides fast flow quantification within 35 min and a flexible reconstruction framework.
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http://dx.doi.org/10.1186/s12968-019-0566-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792269PMC
October 2019

Platelet surface expression of cyclophilin A is associated with increased mortality in patients with symptomatic coronary artery disease.

J Thromb Haemost 2020 01 20;18(1):234-242. Epub 2019 Oct 20.

Department of Cardiology, University Hospital Tübingen, Tübingen, Germany.

Background: Cyclophilin A (CyPA) is an important intracellular molecule mediating essential cellular functions such as signaling and protein folding. Enhanced CyPA platelet surface expression is associated with hypertension and hypercholesterolemia in patients with stable coronary artery disease (CAD). In patients with acute myocardial infarction CyPA platelet surface expression is significantly decreased. The aim of this study was to investigate possible associations of CyPA platelet surface expression and a clinically relevant CyPA single-nucleotide polymorphism (CyPA PPIA rs6850) with prognosis in patients with symptomatic cardiovascular disease.

Materials And Methods: Blood was obtained from 335 consecutive patients with symptomatic CAD. All patients were followed up for 1080 days for endpoints all-cause death, myocardial infarction (MI), ischemic stroke, and bleeding. The primary combined endpoint was defined as a composite of all-cause death and/or MI and/or ischemic stroke. Cyclophilin A platelet surface expression levels less than or equal to the median were significantly associated with a worse prognosis (combined endpoint and all-cause death) when compared to CyPA greater than the median. Genotyping for CyPA PPIA rs6850 was performed in 752 patients with symptomatic CAD. Homozygous carriers of the minor allele showed a significantly worse cumulative event-free survival for both combined endpoint and MI when compared to carriers of the major allele.

Conclusion: The CyPA platelet surface expression is associated with mortality whereas CyPA PPIA rs6850 is associated with recurrent MI in patients with symptomatic CAD. Cyclophilin A might offer a new biomarker for risk stratification and tailoring therapies in patients with cardiovascular disease.
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http://dx.doi.org/10.1111/jth.14635DOI Listing
January 2020

The aorta can act as a site of naïve CD4+ T-cell priming.

Cardiovasc Res 2020 02;116(2):306-316

Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Sir Graeme Davies Building, 120 University Place, Glasgow G12 8TA, UK.

Aims: Aortic adaptive immunity plays a role in atherosclerosis; however, the precise mechanisms leading to T-cell activation in the arterial wall remain poorly understood.

Methods And Results: Here, we have identified naïve T cells in the aorta of wild-type and T-cell receptor transgenic mice and we demonstrate that naïve T cells can be primed directly in the vessel wall with both kinetics and frequency of T-cell activation found to be similar to splenic and lymphoid T cells. Aortic homing of naïve T cells is regulated at least in part by the P-selectin glycosylated ligand-1 receptor. In experimental atherosclerosis the aorta supports CD4+ T-cell activation selectively driving Th1 polarization. By contrast, secondary lymphoid organs display Treg expansion.

Conclusion: Our results demonstrate that the aorta can support T-cell priming and that naïve T cells traffic between the circulation and vessel wall. These data underpin the paradigm that local priming of T cells specific for plaque antigens contributes to atherosclerosis progression.
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http://dx.doi.org/10.1093/cvr/cvz102DOI Listing
February 2020

Inhibition of platelet GPVI induces intratumor hemorrhage and increases efficacy of chemotherapy in mice.

Blood 2019 06 5;133(25):2696-2706. Epub 2019 Apr 5.

Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.

Maintenance of tumor vasculature integrity is indispensable for tumor growth and thus affects tumor progression. Previous studies have identified platelets as major regulators of tumor vascular integrity, as their depletion selectively rendered tumor vessels highly permeable and caused massive intratumoral hemorrhage. While these results established platelets as potential targets for antitumor therapy, their depletion is not a treatment option due to their essential role in hemostasis. Thus, a detailed understanding of how platelets safeguard vascular integrity in tumors is urgently demanded. Here, we show for the first time that functional inhibition of glycoprotein VI (GPVI) on the platelet surface with an antibody (JAQ1) F(ab) fragment rapidly induces tumor hemorrhage and diminishes tumor growth similar to complete platelet depletion while not inducing systemic bleeding complications. The intratumor bleeding and tumor growth arrest could be reverted by depletion of Ly6G cells, confirming them to be responsible for the induction of bleeding and necrosis within the tumor. In addition, JAQ1 F(ab)-mediated GPVI inhibition increased intratumoral accumulation of coadministered chemotherapeutic agents, such as Doxil and paclitaxel, thereby resulting in a profound antitumor effect. In summary, our findings identify platelet GPVI as a key regulator of vascular integrity specifically in growing tumors and could serve as a basis for the development of antitumor strategies based on the interference with platelet function.
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http://dx.doi.org/10.1182/blood.2018877043DOI Listing
June 2019

Neutrophils promote atherosclerotic plaque destabilization in a mouse model of endotoxinaemia.

Cardiovasc Res 2018 10;114(12):1573-1574

Institute of Experimental Biomedicine, University Hospital Würzburg, Josef-Schneider-Str. 2, Würzburg, Germany.

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http://dx.doi.org/10.1093/cvr/cvy168DOI Listing
October 2018

LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy.

Oncogene 2018 09 21;37(36):4921-4940. Epub 2018 May 21.

Institute of Anatomy and Cell Biology II, Universität Würzburg, Koellikerstrasse 6, 97070, Würzburg, Germany.

The potential of altering the tumor ECM to improve drug response remains fairly unexplored. To identify targets for modification of the ECM aiming to improve drug response and overcome resistance, we analyzed expression data sets from pre-treatment patient cohorts. Cross-evaluation identified a subset of chemoresistant tumors characterized by increased expression of collagens and collagen-stabilizing enzymes. We demonstrate that strong collagen expression and stabilization sets off a vicious circle of self-propagating hypoxia, malignant signaling, and aberrant angiogenesis that can be broken by an appropriate auxiliary intervention: Interfering with collagen stabilization by inhibition of lysyl oxidases significantly enhanced response to chemotherapy in various tumor models, even in metastatic disease. Inhibition of collagen stabilization by itself can reduce or enhance tumor growth depending on the tumor type. The mechanistical basis for this behavior is the dependence of the individual tumor on nutritional supply on one hand and on high tissue stiffness for FAK signaling on the other.
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http://dx.doi.org/10.1038/s41388-018-0320-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127085PMC
September 2018

Cutting Edge: Imbalanced Cation Homeostasis in MAGT1-Deficient B Cells Dysregulates B Cell Development and Signaling in Mice.

J Immunol 2018 04 26;200(8):2529-2534. Epub 2018 Mar 26.

Institute of Experimental Biomedicine, University Hospital Würzburg, 97080 Würzburg, Germany;

Cation homeostasis, in relation to various immune-suppressive diseases, is a novel field of investigation. Recently, patients with a loss-of-function mutation in magnesium transporter 1 (MAGT1) were reported to present a dysregulated Mg homeostasis in T lymphocytes. Using -knockout mice ( ), we show that Mg homeostasis was impaired in B cells and Ca influx was increased after BCR stimulation, whereas T and NK cell function was unaffected. Consequently, mutant B cells displayed an increased phosphorylation of BCR-related proteins differentially affecting protein kinase C activation. These in vitro findings translated into increased frequencies of CD19 B cells and marginal zone B cells and decreased frequencies of plasma cells among CD45 splenocytes in vivo. Altogether, our study demonstrates for the first time, to our knowledge, that abolished MAGT1 function causes imbalanced cation homeostasis and developmental responses in B cells. Therefore, this study might contribute to a further understanding of B cell-related pathologies.
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http://dx.doi.org/10.4049/jimmunol.1701467DOI Listing
April 2018

Atlas of the Immune Cell Repertoire in Mouse Atherosclerosis Defined by Single-Cell RNA-Sequencing and Mass Cytometry.

Circ Res 2018 06 15;122(12):1675-1688. Epub 2018 Mar 15.

Institute of Experimental Biomedicine, University Hospital Würzburg, Germany (C.C., A.Z.)

Rationale: Atherosclerosis is a chronic inflammatory disease that is driven by the interplay of pro- and anti-inflammatory leukocytes in the aorta. Yet, the phenotypic and transcriptional diversity of aortic leukocytes is poorly understood.

Objective: We characterized leukocytes from healthy and atherosclerotic mouse aortas in-depth by single-cell RNA-sequencing and mass cytometry (cytometry by time of flight) to define an atlas of the immune cell landscape in atherosclerosis.

Methods And Results: Using single-cell RNA-sequencing of aortic leukocytes from chow diet- and Western diet-fed and mice, we detected 11 principal leukocyte clusters with distinct phenotypic and spatial characteristics while the cellular repertoire in healthy aortas was less diverse. Gene set enrichment analysis on the single-cell level established that multiple pathways, such as for lipid metabolism, proliferation, and cytokine secretion, were confined to particular leukocyte clusters. Leukocyte populations were differentially regulated in atherosclerotic and mice. We confirmed the phenotypic diversity of these clusters with a novel mass cytometry 35-marker panel with metal-labeled antibodies and conventional flow cytometry. Cell populations retrieved by these protein-based approaches were highly correlated to transcriptionally defined clusters. In an integrated screening strategy of single-cell RNA-sequencing, mass cytometry, and fluorescence-activated cell sorting, we detected 3 principal B-cell subsets with alterations in surface markers, functional pathways, and in vitro cytokine secretion. Leukocyte cluster gene signatures revealed leukocyte frequencies in 126 human plaques by a genetic deconvolution strategy. This approach revealed that human carotid plaques and microdissected mouse plaques were mostly populated by macrophages, T-cells, and monocytes. In addition, the frequency of genetically defined leukocyte populations in carotid plaques predicted cardiovascular events in patients.

Conclusions: The definition of leukocyte diversity by high-dimensional analyses enables a fine-grained analysis of aortic leukocyte subsets, reveals new immunologic mechanisms and cell-type-specific pathways, and establishes a functional relevance for lesional leukocytes in human atherosclerosis.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.312513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993603PMC
June 2018

Single-Cell RNA-Seq Reveals the Transcriptional Landscape and Heterogeneity of Aortic Macrophages in Murine Atherosclerosis.

Circ Res 2018 06 15;122(12):1661-1674. Epub 2018 Mar 15.

From the Institute of Experimental Biomedicine (C.C., A.Z.)

Rationale: It is assumed that atherosclerotic arteries contain several macrophage subsets endowed with specific functions. The precise identity of these subsets is poorly characterized as they have been defined by the expression of a restricted number of markers.

Objective: We have applied single-cell RNA sequencing as an unbiased profiling strategy to interrogate and classify aortic macrophage heterogeneity at the single-cell level in atherosclerosis.

Method And Results: We performed single-cell RNA sequencing of total aortic CD45 cells extracted from the nondiseased (chow fed) and atherosclerotic (11 weeks of high-fat diet) aorta of low-density lipoprotein receptor-deficient () mice. Unsupervised clustering singled out 13 distinct aortic cell clusters. Among the myeloid cell populations, resident-like macrophages with a gene expression profile similar to aortic resident macrophages were found in healthy and diseased aortas, whereas monocytes, monocyte-derived dendritic cells, and 2 populations of macrophages were almost exclusively detectable in atherosclerotic aortas, comprising inflammatory macrophages showing enrichment in and previously undescribed TREM2 (triggered receptor expressed on myeloid cells 2) macrophages showing enrichment in . Differential gene expression and gene ontology enrichment analyses revealed specific gene expression patterns distinguishing these 3 macrophage subsets and monocyte-derived dendritic cells and uncovered putative functions of each cell type. Notably, TREM2 macrophages seemed to be endowed with specialized functions in lipid metabolism and catabolism and presented a gene expression signature reminiscent of osteoclasts, suggesting a role in lesion calcification. TREM2 expression was moreover detected in human lesional macrophages. Importantly, these macrophage populations were present also in advanced atherosclerosis and in aortas, indicating relevance of our findings in different stages of atherosclerosis and mouse models.

Conclusions: These data unprecedentedly uncovered the transcriptional landscape and phenotypic heterogeneity of aortic macrophages and monocyte-derived dendritic cells in atherosclerotic and identified previously unrecognized macrophage populations and their gene expression signature, suggesting specialized functions. Our findings will open up novel opportunities to explore distinct myeloid cell populations and their functions in atherosclerosis.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.312509DOI Listing
June 2018

Extracellular Matrix Metalloproteinase Inducer EMMPRIN (CD147) in Cardiovascular Disease.

Int J Mol Sci 2018 Feb 8;19(2). Epub 2018 Feb 8.

Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls-Universität Tübingen, 72076 Tübingen, Germany.

The receptor EMMPRIN is involved in the development and progression of cardiovascular diseases and in the pathogenesis of myocardial infarction. There are several binding partners of EMMPRIN mediating the effects of EMMPRIN in cardiovascular diseases. EMMPRIN interaction with most binding partners leads to disease progression by mediating cytokine or chemokine release, the activation of platelets and monocytes, as well as the formation of monocyte-platelet aggregates (MPAs). EMMPRIN is also involved in atherosclerosis by mediating the infiltration of pro-inflammatory cells. There is also evidence that EMMPRIN controls energy metabolism of cells and that EMMPRIN binding partners modulate intracellular glycosylation and trafficking of EMMPRIN towards the cell membrane. In this review, we systematically discuss these multifaceted roles of EMMPRIN and its interaction partners, such as Cyclophilins, in cardiovascular disease.
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http://dx.doi.org/10.3390/ijms19020507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855729PMC
February 2018

Lipase inhibitor orlistat prevents hepatitis B virus infection by targeting an early step in the virus life cycle.

Antiviral Res 2018 03 5;151:4-7. Epub 2018 Jan 5.

Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Trogerstrasse 30, 81675 Munich, Germany; German Center for Infection Research (DZIF), Munich site, Germany. Electronic address:

Hepatitis B Virus (HBV) is a strictly hepatotropic pathogen which is very efficiently targeted to the liver and into its host cell, the hepatocyte. The sodium taurocholate co-transporting polypeptide (NTCP) has been identified as a key virus entry receptor, but the early steps in the virus life cycle are still only barely understood. Here, we investigated the effect of lipase inhibition and lipoprotein uptake on HBV infection using differentiated HepaRG cells and primary human hepatocytes. We found that an excess of triglyceride rich lipoprotein particles in vitro diminished HBV infection and a reduced hepatic virus uptake in vivo if apolipoprotein E is lacking indicating virus transport along with lipoproteins to target hepatocytes. Moreover, we showed that HBV infection of hepatocytes was inhibited by the broadly active lipase inhibitor orlistat, approved as a therapeutic agent which blocks neutral lipid hydrolysis activity. Orlistat treatment targets HBV infection at a post-entry step and inhibited HBV infection during virus inoculation strongly in a dose-dependent manner. In contrast, orlistat had no effect on HBV gene expression or replication or when added after HBV infection. Taken together, our data indicate that HBV connects to the hepatotropic lipoprotein metabolism and that inhibition of cellular hepatic lipase(s) may allow to target early steps of HBV infection.
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http://dx.doi.org/10.1016/j.antiviral.2018.01.001DOI Listing
March 2018

Using the Sleeve Technique in a Mouse Model of Aortic Transplantation - An Instructional Video.

J Vis Exp 2017 10 22(128). Epub 2017 Oct 22.

Institute of Molecular Cardiovascular Research, University Hospital, RWTH Aachen University Department of Medicine.

Orthotopic aortic transplantation using the sleeve technique reduces injury to the aorta with failure rate of only 10-20%. The time to anastomose the aorta in mice using the sleeve method was short and easy averaging 20 min, permitting studies of iso/allo grafts. The following article describes the aortic transplantation procedure used in our laboratory. The mice were anesthetized with a mixture of 1.5% volume isoflurane and 100% oxygen through a face mask. At this point, the segment of the aorta between the renal arteries and its bifurcation was separated from the vena cava, freely prepared and clampedat the proximal and distal segments with a single silk suture. Prior to the removal of the aorta, a saline solution containing heparin was injected into the inferior vena cava. Then the aorta was cut between the clamps and a saline heparin solution was used to flush the lumen. The sleeve technique with monofilament sutures was used in order to transplant the abdominal aorta in the orthotopic position.
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http://dx.doi.org/10.3791/54915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755186PMC
October 2017

Extracellular Cyclophilin A Augments Platelet-Dependent Thrombosis and Thromboinflammation.

Thromb Haemost 2017 11 30;117(11):2063-2078. Epub 2017 Nov 30.

Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls-Universität Tübingen, Tübingen, Germany.

Cyclophilin A (CyPA) is involved in the pathophysiology of several inflammatory and cardiovascular diseases. To our knowledge, there is no specific inhibitor targeting extracellular CyPA without affecting other extracellular cyclophilins or intracellular CyPA functions. In this study, we developed an antibody-based inhibitor of extracellular CyPA and analysed its effects and . To generate a specific antibody, mice and rats were immunized with a peptide containing the extracellular matrix metalloproteinase inducer binding site and various antibody clones were selected and purified. At first, antibodies were tested for their binding capacity to recombinant CyPA and their functional activity. The clone 8H7-mAb was chosen for further experiments. 8H7-mAb reduced the CyPA-induced migration of inflammatory cells and . Furthermore, 8H7-mAb revealed strong antithrombotic effects by inhibiting CyPA-dependent activation of platelets and thrombus formation and . Surprisingly, 8H7-mAb did not influence tail bleeding time or whole blood coagulation parameters. Our study provides first evidence that antibody-based inhibition of extracellular CyPA inhibits thrombosis and thromboinflammation without affecting blood homeostasis. Thus, 8H7-mAb may be a promising compound for thrombi modulation in inflammatory diseases to prevent organ dysfunction.
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http://dx.doi.org/10.1160/TH17-01-0067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885247PMC
November 2017

Cell differentiation defines acute and chronic infection cell types in .

Elife 2017 09 12;6. Epub 2017 Sep 12.

Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.

A central question to biology is how pathogenic bacteria initiate acute or chronic infections. Here we describe a genetic program for cell-fate decision in the opportunistic human pathogen , which generates the phenotypic bifurcation of the cells into two genetically identical but different cell types during the course of an infection. Whereas one cell type promotes the formation of biofilms that contribute to chronic infections, the second type is planktonic and produces the toxins that contribute to acute bacteremia. We identified a bimodal switch in the quorum sensing system that antagonistically regulates the differentiation of these two physiologically distinct cell types. We found that extracellular signals affect the behavior of the bimodal switch and modify the size of the specialized subpopulations in specific colonization niches. For instance, magnesium-enriched colonization niches causes magnesium binding to teichoic acids and increases bacterial cell wall rigidity. This signal triggers a genetic program that ultimately downregulates the bimodal switch. Colonization niches with different magnesium concentrations influence the bimodal system activity, which defines a distinct ratio between these subpopulations; this in turn leads to distinct infection outcomes in vitro and in an in vivo murine infection model. Cell differentiation generates physiological heterogeneity in clonal bacterial infections and helps to determine the distinct infection types.
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http://dx.doi.org/10.7554/eLife.28023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595439PMC
September 2017

Antigen-presenting dendritic cells in atherosclerosis.

Eur J Pharmacol 2017 Dec 16;816:25-31. Epub 2017 Aug 16.

Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany. Electronic address:

Atherosclerosis is characterized by lipid accumulation and chronic inflammation of the arterial wall, involving both innate and adaptive immune responses. Accumulation of lipid-laden macrophages is a key event in atherosclerosis. However, also other immune cells, such as dendritic cells (DC) and T cells, are found within lesions. DCs are classified as a separate lineage of mononuclear phagocytes that arise from progenitors distinct from precursors of monocytes/macrophages. Although a clear attribution of the effects of antigen-presenting cells (APCs) to monocytes/macrophages and DCs is hampered by the use of promiscuous surface markers, recent research has approached to resolve the contribution of bona fide DCs and their subsets, and of plasmacytoidDCs (pDCs) to atherosclerosis. We here discuss the pathogenic and protective mechanisms engaged by APCs in atherosclerosis and highlight current concepts to further address their role in atherosclerosis.
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http://dx.doi.org/10.1016/j.ejphar.2017.08.016DOI Listing
December 2017

Hypercholesterolemia induced cerebral small vessel disease.

PLoS One 2017 10;12(8):e0182822. Epub 2017 Aug 10.

German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.

Background: While hypercholesterolemia plays a causative role for the development of ischemic stroke in large vessels, its significance for cerebral small vessel disease (CSVD) remains unclear. We thus aimed to understand the detailed relationship between hypercholesterolemia and CSVD using the well described Ldlr-/- mouse model.

Methods: We used Ldlr-/- mice (n = 16) and wild-type (WT) mice (n = 15) at the age of 6 and 12 months. Ldlr-/- mice develop high plasma cholesterol levels following a high fat diet. We analyzed cerebral capillaries and arterioles for intravascular erythrocyte accumulations, thrombotic vessel occlusions, blood-brain barrier (BBB) dysfunction and microbleeds.

Results: We found a significant increase in the number of erythrocyte stases in 6 months old Ldlr-/- mice compared to all other groups (P < 0.05). Ldlr-/- animals aged 12 months showed the highest number of thrombotic occlusions while in WT animals hardly any occlusions could be observed (P < 0.001). Compared to WT mice, Ldlr-/- mice did not display significant gray matter BBB breakdown. Microhemorrhages were observed in one Ldlr-/- mouse that was 6 months old. Results did not differ when considering subcortical and cortical regions.

Conclusions: In Ldlr-/- mice, hypercholesterolemia is related to a thrombotic CSVD phenotype, which is different from hypertension-related CSVD that associates with a hemorrhagic CSVD phenotype. Our data demonstrate a relationship between hypercholesterolemia and the development of CSVD. Ldlr-/- mice appear to be an adequate animal model for research into CSVD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182822PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552130PMC
October 2017

Deletion of Batf3-dependent antigen-presenting cells does not affect atherosclerotic lesion formation in mice.

PLoS One 2017 3;12(8):e0181947. Epub 2017 Aug 3.

Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.

Atherosclerosis is the main underlying cause for cardiovascular events such as myocardial infarction and stroke and its development might be influenced by immune cells. Dendritic cells (DCs) bridge innate and adaptive immune responses by presenting antigens to T cells and releasing a variety of cytokines. Several subsets of DCs can be discriminated that engage specific transcriptional pathways for their development. Basic leucine zipper transcription factor ATF-like 3 (Batf3) is required for the development of classical CD8α+ and CD103+ DCs. By crossing mice deficient in Batf3 with atherosclerosis-prone low density lipoprotein receptor (Ldlr-/-)-deficient mice we here aimed to further address the contribution of Batf3-dependent CD8α+ and CD103+ antigen-presenting cells to atherosclerosis. We demonstrate that deficiency in Batf3 entailed mild effects on the immune response in the spleen but did not alter atherosclerotic lesion formation in the aorta or aortic root, nor affected plaque phenotype in low density lipoprotein receptor-deficient mice fed a high fat diet. We thus provide evidence that Batf3-dependent antigen-presenting cells do not have a prominent role in atherosclerosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181947PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542449PMC
October 2017