Refine
Has Fulltext
- yes (27)
Is part of the Bibliography
- yes (27)
Year of publication
Document Type
- Journal article (27)
Language
- English (27) (remove)
Keywords
- atherosclerosis (7)
- LASP1 (3)
- cytotoxic T cells (3)
- inflammation (3)
- 4D flow (2)
- AAA (2)
- CML (2)
- CXCR4 (2)
- WSS (2)
- aorta (2)
- aortic arch (2)
- breast cancer (2)
- dendritic cells (2)
- diet (2)
- infection (2)
- mice (2)
- mouse (2)
- mouse models (2)
- platelets (2)
- pulse wave velocity (2)
- recruitment (2)
- regulatory T cells (2)
- translational research (2)
- wall shear stress (2)
- 4D flow MRI (1)
- AKT1 (1)
- AP-1 (1)
- Aortic arch (1)
- BCR‐ABL (1)
- Batf3 (1)
- CCR2 (1)
- CD147 (1)
- CD8\(^+\) T cells (1)
- CMR (1)
- Cancer models (1)
- Cancer therapeutic resistance (1)
- Cyclophilin A (1)
- DAPI staining (1)
- EMMPRIN (1)
- KAT/HAT (1)
- Mouse (1)
- NF-KAPPA-B (1)
- OSI (1)
- PWV (1)
- Self-navigation (1)
- Staphylococcus aureus (1)
- T cells (1)
- Targeted therapies (1)
- Tumour angiogenesis (1)
- abdominal aortic-aneurysm (1)
- accumulation (1)
- acetylation (1)
- acetyltransferases (1)
- arterial elasticity (1)
- atheriosclerotic lesions (1)
- atherosclerotic vascular disease (1)
- beta (1)
- bone-marrow (1)
- c-Fos (1)
- cardiovascular MRI (1)
- cardiovascular disease (1)
- cardiovascular pharmacology (1)
- carotid arteries (1)
- cell differentiation (1)
- cell staining (1)
- cerebral small vessel disease (1)
- checkpoint inhibitors (1)
- chemokine (1)
- chemokines (1)
- coatings (1)
- deficiency (1)
- dilation (1)
- endothelial cells (1)
- endothelial progenitor cells (1)
- epigenetics (1)
- extracellular matrix (1)
- factor-I (1)
- flow (1)
- flow cytometry (1)
- flow dynamics (1)
- fluorescence microscopy (1)
- fractalkine (1)
- gene expression (1)
- heart (1)
- heart-failure (1)
- histologic diversity (1)
- histology (1)
- histone acetylation (1)
- humans (1)
- hypercholesterolemia (1)
- hypercholeterolemia (1)
- hyperlipedemic mice (1)
- immunoglobulin superfamily (1)
- immunotherapy (1)
- increases atherosclersosis (1)
- indoleamine 2,3-dioxygenase (1)
- inflammatory sites (1)
- inhibition (1)
- large animal models (1)
- left-ventricular function (1)
- lymphocyte differentiation (1)
- macrophages (1)
- magnetic resonance imaging (1)
- mapping (1)
- marcophages (1)
- matrix metalloproteinases (1)
- miRNA expression (1)
- microscopy (1)
- mobilization (1)
- monocyte (1)
- monocyte subset (1)
- monocyte-platelet aggregates (1)
- monocytes (1)
- mouse model (1)
- nilotinib (1)
- nutritional deficiencies (1)
- organoid (1)
- pathogenic bacteria (1)
- pathway (1)
- pathway analysis (1)
- peripheral artery occlusive disease (1)
- pig (1)
- plaque (1)
- plaque characteristics (1)
- polymers (1)
- popliteal aneurysm (1)
- precursor cells (1)
- prediction (1)
- quantification (1)
- radial (1)
- rat model (1)
- receptor (1)
- remodelling (1)
- research infrastructure (1)
- rupture (1)
- self-navigation (1)
- single cell RNA sequencing (1)
- spleen (1)
- stem cells (1)
- stent implantation (1)
- subsets (1)
- therapy (1)
- ultrahigh-field MRI (1)
Institute
- Institut für Experimentelle Biomedizin (15)
- Institut für Klinische Biochemie und Pathobiochemie (7)
- Rudolf-Virchow-Zentrum (6)
- Medizinische Klinik und Poliklinik I (5)
- Physikalisches Institut (4)
- Deutsches Zentrum für Herzinsuffizienz (DZHI) (3)
- Institut für Anatomie und Zellbiologie (2)
- Institut für diagnostische und interventionelle Neuroradiologie (ehem. Abteilung für Neuroradiologie) (2)
- Theodor-Boveri-Institut für Biowissenschaften (2)
- Abteilung für Funktionswerkstoffe der Medizin und der Zahnheilkunde (1)
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.
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.
Monocytes are key players in atherosclerotic. Human monocytes display a considerable heterogeneity and at least three subsets can be distinguished. While the role of monocyte subset heterogeneity has already been well investigated in coronary artery disease (CAD), the knowledge about monocytes and their heterogeneity in peripheral artery occlusive disease (PAOD) still is limited. Therefore, we aimed to investigate monocyte subset heterogeneity in patients with PAOD. Peripheral blood was obtained from 143 patients suffering from PAOD (Rutherford stage I to VI) and three monocyte subsets were identified by flow cytometry: CD14\(^{++}\)CD16\(^{-}\) classical monocytes, CD14\(^{+}\)CD16\(^{++}\) non-classical monocytes and CD14\(^{++}\)CD16\(^{+}\) intermediate monocytes. Additionally the expression of distinct surface markers (CD106, CD162 and myeloperoxidase MPO) was analyzed. Proportions of CD14\(^{++}\)CD16\(^{+}\) intermediate monocyte levels were significantly increased in advanced stages of PAOD, while classical and non-classical monocytes displayed no such trend. Moreover, CD162 and MPO expression increased significantly in intermediate monocyte subsets in advanced disease stages. Likewise, increased CD162 and MPO expression was noted in CD14\(^{++}\)CD16\(^{-}\) classical monocytes. These data suggest substantial dynamics in monocyte subset distributions and phenotypes in different stages of PAOD, which can either serve as biomarkers or as potential therapeutic targets to decrease the inflammatory burden in advanced stages of atherosclerosis.
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.
Simultaneous measurements of 3D wall shear stress and pulse wave velocity in the murine aortic arch
(2021)
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\(^2\) in wildtype mice and (1.27 ± 0.10) N/m\(^2\) 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.
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.
Distinct functions of specialized dendritic cell subsets in atherosclerosis and the road ahead
(2014)
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.