@article{AndelovicWinterKampfetal.2021, author = {Andelovic, Kristina and Winter, Patrick and Kampf, Thomas and Xu, Anton and Jakob, Peter Michael and Herold, Volker and Bauer, Wolfgang Rudolf and Zernecke, Alma}, title = {2D Projection Maps of WSS and OSI Reveal Distinct Spatiotemporal Changes in Hemodynamics in the Murine Aorta during Ageing and Atherosclerosis}, series = {Biomedicines}, volume = {9}, journal = {Biomedicines}, number = {12}, issn = {2227-9059}, doi = {10.3390/biomedicines9121856}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252164}, year = {2021}, abstract = {Growth, ageing and atherosclerotic plaque development alter the biomechanical forces acting on the vessel wall. However, monitoring the detailed local changes in wall shear stress (WSS) at distinct sites of the murine aortic arch over time has been challenging. Here, we studied the temporal and spatial changes in flow, WSS, oscillatory shear index (OSI) and elastic properties of healthy wildtype (WT, n = 5) and atherosclerotic apolipoprotein E-deficient (Apoe\(^{-/-}\), n = 6) mice during ageing and atherosclerosis using high-resolution 4D flow magnetic resonance imaging (MRI). Spatially resolved 2D projection maps of WSS and OSI of the complete aortic arch were generated, allowing the pixel-wise statistical analysis of inter- and intragroup hemodynamic changes over time and local correlations between WSS, pulse wave velocity (PWV), plaque and vessel wall characteristics. The study revealed converse differences of local hemodynamic profiles in healthy WT and atherosclerotic Apoe\(^{-/-}\) mice, and we identified the circumferential WSS as potential marker of plaque size and composition in advanced atherosclerosis and the radial strain as a potential marker for vascular elasticity. Two-dimensional (2D) projection maps of WSS and OSI, including statistical analysis provide a powerful tool to monitor local aortic hemodynamics during ageing and atherosclerosis. The correlation of spatially resolved hemodynamics and plaque characteristics could significantly improve our understanding of the impact of hemodynamics on atherosclerosis, which may be key to understand plaque progression towards vulnerability.}, language = {en} } @article{BuschBuschScholzetal.2016, author = {Busch, Albert and Busch, Martin and Scholz, Claus-J{\"u}rgen and Kellersmann, Richard and Otto, Christoph and Chernogubova, Ekaterina and Maegdefessel, Lars and Zernecke, Alma and Lorenz, Udo}, title = {Aneurysm miRNA Signature Differs, Depending on Disease Localization and Morphology}, series = {International Journal of Molecular Science}, volume = {17}, journal = {International Journal of Molecular Science}, number = {1}, issn = {International Journal of Molecular Science}, doi = {10.3390/ijms17010081}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146422}, pages = {81}, year = {2016}, abstract = {Limited comprehension of aneurysm pathology has led to inconclusive results from clinical trials. miRNAs are key regulators of post-translational gene modification and are useful tools in elucidating key features of aneurysm pathogenesis in distinct entities of abdominal and popliteal aneurysms. Here, surgically harvested specimens from 19 abdominal aortic aneurysm (AAA) and 8 popliteal artery aneurysm (PAA) patients were analyzed for miRNA expression and histologically classified regarding extracellular matrix (ECM) remodeling and inflammation. DIANA-based computational target prediction and pathway enrichment analysis verified our results, as well as previous ones. miRNA-362, -19b-1, -194, -769, -21 and -550 were significantly down-regulated in AAA samples depending on degree of inflammation. Similar or inverse regulation was found for miR-769, 19b-1 and miR-550, -21, whereas miR-194 and -362 were unaltered in PAA. In situ hybridization verified higher expression of miR-550 and -21 in PAA compared to AAA and computational analysis for target genes and pathway enrichment affirmed signal transduction, cell-cell-interaction and cell degradation pathways, in line with previous results. Despite the vague role of miRNAs for potential diagnostic and treatment purposes, the number of candidates from tissue signature studies is increasing. Tissue morphology influences subsequent research, yet comparison of distinct entities of aneurysm disease can unravel core pathways.}, language = {en} } @article{TilstamGijbelsHabbeddineetal.2014, author = {Tilstam, Pathricia V. and Gijbels, Marion J. and Habbeddine, Mohamed and Cudejko, Celine and Asare, Yaw and Theelen, Wendy and Zhou, Baixue and D{\"o}ring, Yvonne and Drechsler, Maik and Pawig, Lukas and Simsekyilmaz, Sakine and Koenen, Rory R. and de Winther, Menno P. J. and Lawrence, Toby and Bernhagen, J{\"u}rgen and Zernecke, Alma and Weber, Christian and Noels, Heidi}, title = {Bone Marrow-Specific Knock-In of a Non-Activatable Ikkα Kinase Mutant Influences Haematopoiesis but Not Atherosclerosis in Apoe-Deficient Mice}, series = {PLOS ONE}, volume = {9}, journal = {PLOS ONE}, number = {2}, doi = {10.1371/journal.pone.0087452}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117450}, pages = {e87452}, year = {2014}, abstract = {Background: The Ikkα kinase, a subunit of the NF-kappa B-activating IKK complex, has emerged as an important regulator of inflammatory gene expression. However, the role of Ikkα-mediated phosphorylation in haematopoiesis and atherogenesis remains unexplored. In this study, we investigated the effect of a bone marrow (BM)-specific activation-resistant Ikk alpha mutant knock-in on haematopoiesis and atherosclerosis in mice. Methods and Results: Apolipoprotein E (Apoe)-deficient mice were transplanted with BM carrying an activation-resistant Ikkα gene (Ikkα(AA/AA) Apoe(-/-)) or with Ikkα(+/+) Apoe(-/-) BM as control and were fed a high-cholesterol diet for 8 or 13 weeks. Interestingly, haematopoietic profiling by flow cytometry revealed a significant decrease in B-cells, regulatory T-cells and effector memory T-cells in Ikkα(AA/AA) Apoe(-/-) BM-chimeras, whereas the naive T-cell population was increased. Surprisingly, no differences were observed in the size, stage or cellular composition of atherosclerotic lesions in the aorta and aortic root of Ikkα(AA/AA) Apoe(-/-) vs Ikkα(+/+) Apoe(-/-) BM-transplanted mice, as shown by histological and immunofluorescent stainings. Necrotic core sizes, apoptosis, and intracellular lipid deposits in aortic root lesions were unaltered. In vitro, BM-derived macrophages from Ikkα(AA/AA) Apoe(-/-) vs Ikkα(+/+) Apoe(-/-) mice did not show significant differences in the uptake of oxidized low-density lipoproteins (oxLDL), and, with the exception of Il-12, the secretion of inflammatory proteins in conditions of Tnf-α or oxLDL stimulation was not significantly altered. Furthermore, serum levels of inflammatory proteins as measured with a cytokine bead array were comparable. Conclusion: Our data reveal an important and previously unrecognized role of haematopoietic Ikkα kinase activation in the homeostasis of B-cells and regulatory T-cells. However, transplantation of Ikkα AA mutant BM did not affect atherosclerosis in Apoe(-/-) mice. This suggests that the diverse functions of Ikkα in haematopoietic cells may counterbalance each other or may not be strong enough to influence atherogenesis, and reveals that targeting haematopoietic Ikkα kinase activity alone does not represent a therapeutic approach.}, language = {en} } @article{SchaeferZernecke2020, author = {Sch{\"a}fer, Sarah and Zernecke, Alma}, title = {CD8\(^+\) T cells in atherosclerosis}, series = {Cells}, volume = {10}, journal = {Cells}, number = {1}, issn = {2073-4409}, doi = {10.3390/cells10010037}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220170}, year = {2020}, abstract = {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 CD25\(^+\)CD8\(^+\) 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.}, language = {en} } @article{GarciaBetancurGoniMorenoHorgeretal.2017, author = {Garc{\´i}a-Betancur, Juan-Carlos and Go{\~n}i-Moreno, Angel and Horger, Thomas and Schott, Melanie and Sharan, Malvika and Eikmeier, Julian and Wohlmuth, Barbara and Zernecke, Alma and Ohlsen, Knut and Kuttler, Christina and Lopez, Daniel}, title = {Cell differentiation defines acute and chronic infection cell types in Staphylococcus aureus}, series = {eLife}, volume = {6}, journal = {eLife}, number = {e28023}, doi = {10.7554/eLife.28023}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170346}, year = {2017}, abstract = {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 Staphylococcus aureus, 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 agr 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 agr bimodal switch and modify the size of the specialized subpopulations in specific colonization niches. For instance, magnesium-enriched colonization niches causes magnesium binding to S. aureusteichoic acids and increases bacterial cell wall rigidity. This signal triggers a genetic program that ultimately downregulates the agr 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.}, language = {en} } @article{ProjahnSimsekyilmazSinghetal.2014, author = {Projahn, Delia and Simsekyilmaz, Sakine and Singh, Smriti and Kanzler, Isabella and Kramp, Birgit K. and Langer, Marcella and Burlacu, Alexandrina and Bernhagen, J{\"u}rgen and Klee, Doris and Zernecke, Alma and Hackeng, Tilman M. and Groll, J{\"u}rgen and Weber, Christian and Liehn, Elisa A. and Koenen, Roy R.}, title = {Controlled intramyocardial release of engineered chemokines by biodegradable hydrogels as a treatment approach of myocardial infarction}, series = {Journal of Cellular and Molecular Medicine}, volume = {18}, journal = {Journal of Cellular and Molecular Medicine}, number = {5}, issn = {1582-4934}, doi = {10.1111/jcmm.12225}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116597}, pages = {790-800}, year = {2014}, abstract = {Myocardial infarction (MI) induces a complex inflammatory immune response, followed by the remodelling of the heart muscle and scar formation. The rapid regeneration of the blood vessel network system by the attraction of hematopoietic stem cells is beneficial for heart function. Despite the important role of chemokines in these processes, their use in clinical practice has so far been limited by their limited availability over a long time-span in vivo. Here, a method is presented to increase physiological availability of chemokines at the site of injury over a defined time-span and simultaneously control their release using biodegradable hydrogels. Two different biodegradable hydrogels were implemented, a fast degradable hydrogel (FDH) for delivering Met-CCL5 over 24hrs and a slow degradable hydrogel (SDH) for a gradual release of protease-resistant CXCL12 (S4V) over 4weeks. We demonstrate that the time-controlled release using Met-CCL5-FDH and CXCL12 (S4V)-SDH suppressed initial neutrophil infiltration, promoted neovascularization and reduced apoptosis in the infarcted myocardium. Thus, we were able to significantly preserve the cardiac function after MI. This study demonstrates that time-controlled, biopolymer-mediated delivery of chemokines represents a novel and feasible strategy to support the endogenous reparatory mechanisms after MI and may compliment cell-based therapies.}, language = {en} } @article{RosaButtHopperetal.2022, author = {Rosa, Annabelle and Butt, Elke and Hopper, Christopher P. and Loroch, Stefan and Bender, Markus and Schulze, Harald and Sickmann, Albert and Vorlova, Sandra and Seizer, Peter and Heinzmann, David and Zernecke, Alma}, title = {Cyclophilin a is not acetylated at lysine-82 and lysine-125 in resting and stimulated platelets}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {3}, issn = {1422-0067}, doi = {10.3390/ijms23031469}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284011}, year = {2022}, abstract = {Cyclophilin A (CyPA) is widely expressed by all prokaryotic and eukaryotic cells. Upon activation, CyPA can be released into the extracellular space to engage in a variety of functions, such as interaction with the CD147 receptor, that contribute to the pathogenesis of cardiovascular diseases. CyPA was recently found to undergo acetylation at K82 and K125, two lysine residues conserved in most species, and these modifications are required for secretion of CyPA in response to cell activation in vascular smooth muscle cells. Herein we addressed whether acetylation at these sites is also required for the release of CyPA from platelets based on the potential for local delivery of CyPA that may exacerbate cardiovascular disease events. Western blot analyses confirmed the presence of CyPA in human and mouse platelets. Thrombin stimulation resulted in CyPA release from platelets; however, no acetylation was observed—neither in cell lysates nor in supernatants of both untreated and activated platelets, nor after immunoprecipitation of CyPA from platelets. Shotgun proteomics detected two CyPA peptide precursors in the recombinant protein, acetylated at K28, but again, no acetylation was found in CyPA derived from resting or stimulated platelets. Our findings suggest that acetylation of CyPA is not a major protein modification in platelets and that CyPA acetylation is not required for its secretion from platelets.}, language = {en} } @article{GilPulidoCochainLippertetal.2017, author = {Gil-Pulido, Jesus and Cochain, Clement and Lippert, Malte A. and Schneider, Nicole and Butt, Elke and Am{\´e}zaga, N{\´u}ria and Zernecke, Alma}, title = {Deletion of Batf3-dependent antigen-presenting cells does not affect atherosclerotic lesion formation in mice}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {8}, doi = {10.1371/journal.pone.0181947}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170535}, pages = {e0181947}, year = {2017}, abstract = {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.}, language = {en} } @article{BuschWesthofenKochetal.2014, author = {Busch, Martin and Westhofen, Thilo C. and Koch, Miriam and Lutz, Manfred B. and Zernecke, Alma}, title = {Dendritic Cell Subset Distributions in the Aorta in Healthy and Atherosclerotic Mice}, series = {PLoS ONE}, volume = {9}, journal = {PLoS ONE}, number = {2}, issn = {1932-6203}, doi = {10.1371/journal.pone.0088452}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119907}, pages = {e88452}, year = {2014}, abstract = {Dendritic cells (DCs) can be sub-divided into various subsets that play specialized roles in priming of adaptive immune responses. Atherosclerosis is regarded as a chronic inflammatory disease of the vessel wall and DCs can be found in non-inflamed and diseased arteries. We here performed a systematic analyses of DCs subsets during atherogenesis. Our data indicate that distinct DC subsets can be localized in the vessel wall. In C57BL/6 and low density lipoprotein receptor-deficient (Ldlr-/-) mice, CD11c+ MHCII+ DCs could be discriminated into CD103- CD11b+F4/80+, CD11b+F4/80- and CD11b-F4/80- DCs and CD103+ CD11b-F4/80- DCs. Except for CD103- CD11b- F4/80- DCs, these subsets expanded in high fat diet-fed Ldlr-/- mice. Signal-regulatory protein (Sirp)-α was detected on aortic macrophages, CD11b+ DCs, and partially on CD103- CD11b- F4/80- but not on CD103+ DCs. Notably, in FMS-like tyrosine kinase 3-ligand-deficient (Flt3l-/-) mice, a specific loss of CD103+ DCs but also CD103- CD11b+ F4/80- DCs was evidenced. Aortic CD103+ and CD11b+ F4/80- CD103- DCs may thus belong to conventional rather than monocyte-derived DCs, given their dependence on Flt3L-signalling. CD64, postulated to distinguish macrophages from DCs, could not be detected on DC subsets under physiological conditions, but appeared in a fraction of CD103- CD11b+ F4/80- and CD11b+ F4/80+ cells in atherosclerotic Ldlr-/- mice. The emergence of CD64 expression in atherosclerosis may indicate that CD11b+ F4/80- DCs similar to CD11b+ F4/80+ DCs are at least in part derived from immigrated monocytes during atherosclerotic lesion formation. Our data advance our knowledge about the presence of distinct DC subsets and their accumulation characteristics in atherosclerosis, and may help to assist in future studies aiming at specific DC-based therapeutic strategies for the treatment of chronic vascular inflammation.}, language = {en} } @article{SoehnleinDrechslerDoeringetal.2013, author = {Soehnlein, Oliver and Drechsler, Maik and D{\"o}ring, Yvonne and Lievens, Dirk and Hartwig, Helene and Kemmerich, Klaus and Ortega-G{\´o}mez, Almudena and Mandl, Manuela and Vijayan, Santosh and Projahn, Delia and Garlichs, Christoph D. and Koenen, Rory R. and Hristov, Mihail and Lutgens, Esther and Zernecke, Alma and Weber, Christian}, title = {Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes}, series = {EMBO Molecular Medicine}, volume = {5}, journal = {EMBO Molecular Medicine}, issn = {1757-4676}, doi = {10.1002/emmm.201201717}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122204}, pages = {471-481}, year = {2013}, abstract = {We used a novel approach of cytostatically induced leucocyte depletion and subsequent reconstitution with leucocytes deprived of classical \((inflammatory/Gr1^{hi})\) or non-classical \((resident/Gr1^{lo})\) monocytes to dissect their differential role in atheroprogression under high-fat diet (HFD). Apolipoprotein E-deficient \((Apoe^{-/-})\) mice lacking classical but not non-classical monocytes displayed reduced lesion size and macrophage and apoptotic cell content. Conversely, HFD induced a selective expansion of classical monocytes in blood and bone marrow. Increased CXCL1 levels accompanied by higher expression of its receptor CXCR2 on classical monocytes and inhibition of monocytosis by CXCL1-neutralization indicated a preferential role for the CXCL1/CXCR2 axis in mobilizing classical monocytes during hypercholesterolemia. Studies correlating circulating and lesional classical monocytes in gene-deficient \(Apoe^{-/-}\) mice, adoptive transfer of gene-deficient cells and pharmacological modulation during intravital microscopy of the carotid artery revealed a crucial function of CCR1 and CCR5 but not CCR2 or \(CX_3CR1\) in classical monocyte recruitment to atherosclerotic vessels. Collectively, these data establish the impact of classical monocytes on atheroprogression, identify a sequential role of CXCL1 in their mobilization and CCR1/CCR5 in their recruitment.}, language = {en} } @article{Zernecke2014, author = {Zernecke, Alma}, title = {Distinct functions of specialized dendritic cell subsets in atherosclerosis and the road ahead}, series = {Scientifica}, volume = {2014}, journal = {Scientifica}, doi = {10.1155/2014/952625}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120241}, pages = {952625}, year = {2014}, abstract = {Atherosclerotic vascular disease is modulated by immune mechanisms. Dendritic cells (DCs) and T cells are present within atherosclerotic lesions and function as central players in the initiation and modulation of adaptive immune responses. In previous years, we have studied the functional contribution of distinct DC subsets in disease development, namely, that of CCL17-expressing DCs as well as that of plasmacytoid DCs that play specialized roles in disease development. This review focuses on important findings gathered in these studies and dissects the multifaceted contribution of CCL17-expressing DCs and pDCs to the pathogenesis of atherosclerosis. Furthermore, an outlook on future challenges faced when studying DCs in this detrimental disease are provided, and hurdles that will need to be overcome in order to enable a better understanding of the contribution of DCs to atherogenesis are discussed, a prerequisite for their therapeutic targeting in atherosclerosis.}, language = {en} } @article{RowinskaGorressenMerxetal.2014, author = {Rowinska, Zuzanna and Gorressen, Simone and Merx, Marc W. and Koeppel, Thomas A. and Liehn, Elisa A. and Zernecke, Alma}, title = {Establishment of a New Murine Elastase-Induced Aneurysm Model Combined with Transplantation}, series = {PLOS ONE}, volume = {9}, journal = {PLOS ONE}, number = {7}, issn = {1932-6203}, doi = {10.1371/journal.pone.0102648}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115774}, pages = {e102648}, year = {2014}, abstract = {Introduction: The aim of our study was to develop a reproducible murine model of elastase-induced aneurysm formation combined with aortic transplantation. Methods: Adult male mice (n = 6-9 per group) underwent infrarenal, orthotopic transplantation of the aorta treated with elastase or left untreated. Subsequently, both groups of mice were monitored by ultrasound until 7 weeks after grafting. Results: Mice receiving an elastase-pretreated aorta developed aneurysms and exhibited a significantly increased diastolic vessel diameter compared to control grafted mice at 7 week after surgery (1.11 +/- 0.10 mm vs. 0.75 +/- 0.03 mm; p <= 0.001). Histopathological examination revealed disruption of medial elastin, an increase in collagen content and smooth muscle cells, and neointima formation in aneurysm grafts. Conclusions: We developed a reproducible murine model of elastase-induced aneurysm combined with aortic transplantation. This model may be suitable to investigate aneurysm-specific inflammatory processes and for use in gene-targeted animals.}, language = {en} } @article{AndelovicWinterJakobetal.2021, author = {Andelovic, Kristina and Winter, Patrick and Jakob, Peter Michael and Bauer, Wolfgang Rudolf and Herold, Volker and Zernecke, Alma}, title = {Evaluation of plaque characteristics and inflammation using magnetic resonance imaging}, series = {Biomedicines}, volume = {9}, journal = {Biomedicines}, number = {2}, issn = {2227-9059}, doi = {10.3390/biomedicines9020185}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228839}, year = {2021}, abstract = {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.}, language = {en} } @article{UngernSternbergZerneckeSeizer2018, author = {Ungern-Sternberg, Saskia N. I. von and Zernecke, Alma and Seizer, Peter}, title = {Extracellular matrix metalloproteinase inducer EMMPRIN (CD147) in cardiovascular disease}, series = {International Journal of Molecular Sciences}, volume = {19}, journal = {International Journal of Molecular Sciences}, number = {2}, issn = {1422-0067}, doi = {10.3390/ijms19020507}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285014}, year = {2018}, abstract = {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.}, language = {en} } @article{WinterAndelovicKampfetal.2019, author = {Winter, Patrick and Andelovic, Kristina and Kampf, Thomas and Gutjahr, Fabian Tobias and Heidenreich, Julius and Zernecke, Alma and Bauer, Wolfgang Rudolf and Jakob, Peter Michael and Herold, Volker}, title = {Fast self-navigated wall shear stress measurements in the murine aortic archusing radial 4D-phase contrast cardiovascular magnetic resonance at 17.6 T}, series = {Journal of Cardiovascular Magnetic Resonance}, volume = {21}, journal = {Journal of Cardiovascular Magnetic Resonance}, doi = {10.1186/s12968-019-0566-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201120}, pages = {64}, year = {2019}, abstract = {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 B0 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/m2, 0.28 ± 0.24 N/m2 and - 0.21 ± 0.19 N/m2, 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.}, language = {en} } @article{HanTaniosReepsetal.2016, author = {Han, Yanshuo and Tanios, Fadwa and Reeps, Christian and Zhang, Jian and Schwamborn, Kristina and Eckstein, Hans-Henning and Zernecke, Alma and Pelisek, Jaroslav}, title = {Histone acetylation and histone acetyltransferases show significant alterations in human abdominal aortic aneurysm}, series = {Clinical Epigenetics}, volume = {8}, journal = {Clinical Epigenetics}, number = {3}, doi = {10.1186/s13148-016-0169-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-162557}, year = {2016}, abstract = {Background Epigenetic modifications may play a relevant role in the pathogenesis of human abdominal aortic aneurysm (AAA). The aim of the study was therefore to investigate histone acetylation and expression of corresponding lysine [K] histone acetyltransferases (KATs) in AAA. Results A comparative study of AAA tissue samples (n = 37, open surgical intervention) and healthy aortae (n = 12, trauma surgery) was performed using quantitative PCR, immunohistochemistry (IHC), and Western blot. Expression of the KAT families GNAT (KAT2A, KAT2B), p300/CBP (KAT3A, KAT3B), and MYST (KAT5, KAT6A, KAT6B, KAT7, KAT8) was significantly higher in AAA than in controls (P ≤ 0.019). Highest expression was observed for KAT2B, KAT3A, KAT3B, and KAT6B (P ≤ 0.007). Expression of KAT2B significantly correlated with KAT3A, KAT3B, and KAT6B (r = 0.705, 0.564, and 0.528, respectively, P < 0.001), and KAT6B with KAT3A, KAT3B, and KAT6A (r = 0.407, 0.500, and 0.531, respectively, P < 0.05). Localization of highly expressed KAT2B, KAT3B, and KAT6B was further characterized by immunostaining. Significant correlations were observed between KAT2B with endothelial cells (ECs) (r = 0.486, P < 0.01), KAT3B with T cells and macrophages, (r = 0.421 and r = 0.351, respectively, P < 0.05), KAT6A with intramural ECs (r = 0.541, P < 0.001) and with a contractile phenotype of smooth muscle cells (SMCs) (r = 0.425, P < 0.01), and KAT6B with T cells (r = 0.553, P < 0.001). Furthermore, KAT2B was associated with AAA diameter (r = 0.382, P < 0.05), and KAT3B, KAT6A, and KAT6B correlated negatively with blood urea nitrogen (r = -0.403, -0.408, -0.478, P < 0.05). In addtion, acetylation of the histone substrates H3K9, H3K18 and H3K14 was increased in AAA compared to control aortae. Conclusions Our results demonstrate that aberrant epigenetic modifications such as changes in the expression of KATs and acetylation of corresponding histones are present in AAA. These findings may provide new insight in the pathomechanism of AAA.}, language = {en} } @article{KraftSchuhmannGarzetal.2017, author = {Kraft, Peter and Schuhmann, Michael K. and Garz, Cornelia and Jandke, Solveig and Urlaub, Daniela and Mencl, Stine and Zernecke, Alma and Heinze, Hans-Jochen and Carare, Roxana O. and Kleinschnitz, Christoph and Schreiber, Stefanie}, title = {Hypercholesterolemia induced cerebral small vessel disease}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {8}, doi = {10.1371/journal.pone.0182822}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170493}, pages = {e0182822}, year = {2017}, abstract = {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.}, language = {en} } @article{HerrmannMuellerOrthetal.2020, author = {Herrmann, Andreas B. and M{\"u}ller, Martha-Lena and Orth, Martin F. and M{\"u}ller, J{\"o}rg P. and Zernecke, Alma and Hochhaus, Andreas and Ernst, Thomas and Butt, Elke and Frietsch, Jochen J.}, title = {Knockout of LASP1 in CXCR4 expressing CML cells promotes cell persistence, proliferation and TKI resistance}, series = {Journal of Cellular and Molecular Medicine}, volume = {24}, journal = {Journal of Cellular and Molecular Medicine}, number = {5}, doi = {10.1111/jcmm.14910}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214122}, pages = {2942 -- 2955}, year = {2020}, abstract = {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.}, language = {en} } @article{RossowVeitlVorlovaetal.2018, author = {Rossow, Leonie and Veitl, Simona and Vorlov{\´a}, Sandra and Wax, Jacqueline K. and Kuhn, Anja E. and Maltzahn, Verena and Upcin, Berin and Karl, Franziska and Hoffmann, Helene and G{\"a}tzner, Sabine and Kallius, Matthias and Nandigama, Rajender and Scheld, Daniela and Irmak, Ster and Herterich, Sabine and Zernecke, Alma and Erg{\"u}n, S{\"u}leyman and Henke, Erik}, title = {LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy}, series = {Oncogene}, volume = {37}, journal = {Oncogene}, doi = {10.1038/s41388-018-0320-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227008}, pages = {4921-4940}, year = {2018}, abstract = {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.}, language = {en} } @article{WuZhaoHochreinetal.2023, author = {Wu, Hao and Zhao, Xiufeng and Hochrein, Sophia M. and Eckstein, Miriam and Gubert, Gabriela F. and Kn{\"o}pper, Konrad and Mansilla, Ana Maria and {\"O}ner, Arman and Doucet-Ladev{\`e}ze, Remi and Schmitz, Werner and Ghesqui{\`e}re, Bart and Theurich, Sebastian and Dudek, Jan and Gasteiger, Georg and Zernecke, Alma and Kobold, Sebastian and Kastenm{\"u}ller, Wolfgang and Vaeth, Martin}, title = {Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming}, series = {Nature Communications}, volume = {14}, journal = {Nature Communications}, doi = {10.1038/s41467-023-42634-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-358052}, year = {2023}, abstract = {T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.}, language = {en} }