@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{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} } @phdthesis{Busch2013, author = {Busch, Martin}, title = {Aortic Dendritic Cell Subsets in Healthy and Atherosclerotic Mice and The Role of the miR-17~92 Cluster in Dendritic Cells}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-71683}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Atherosclerosis is accepted to be a chronic inflammatory disease of the arterial vessel wall. Several cellular subsets of the immune system are involved in its initiation and progression, such as monocytes, macrophages, T and B cells. Recent research has demonstrated that dendritic cells (DCs) contribute to atherosclerosis, too. DCs are defined by their ability to sense and phagocyte antigens, to migrate and to prime other immune cells, such as T cells. Although all DCs share these functional characteristics, they are heterogeneous with respect to phenotype and origin. Several markers have been used to describe DCs in different lymphoid and non-lymphoid organs; however, none of them has proven to be unambiguous. The expression of surface molecules is highly variable depending on the state of activation and the surrounding tissue. Furthermore, DCs in the aorta or the atherosclerotic plaque can be derived from designated precursor cells or from monocytes. In addition, DCs share both their marker expression and their functional characteristics with other myeloid cells like monocytes and macrophages. The repertoire of aortic DCs in healthy and atherosclerotic mice has just recently started to be explored, but yet there is no systemic study available, which describes the aortic DC compartment. Because it is conceivable that distinct aortic DC subsets exert dedicated functions, a detailed description of vascular DCs is required. The first part of this thesis characterizes DC subsets in healthy and atherosclerotic mice. It describes a previously unrecognized DC subset and also sheds light on the origin of vascular DCs. In recent years, microRNAs (miRNAs) have been demonstrated to regulate several cellular functions, such as apoptosis, differentiation, development or proliferation. Although several cell types have been characterized extensively with regard to the miRNAs involved in their regulation, only few studies are available that focus on the role of miRNAs in DCs. Because an improved understanding of the regulation of DC functions would allow for new therapeutic options, research on miRNAs in DCs is required. The second part of this thesis focuses on the role of the miRNA cluster miR- 17~92 in DCs by exploring its functions in healthy and atherosclerotic mice. This thesis clearly demonstrates for the first time an anti-inflammatory and atheroprotective role for the miR17-92 cluster. A model for its mechanism is suggested.}, subject = {Aorta}, language = {en} } @article{CochainChaudhariKochetal.2014, author = {Cochain, Clement and Chaudhari, Sweena M. and Koch, Miriam and Wiendl, Heinz and Eckstein, Hans-Henning and Zernecke, Alma}, title = {Programmed Cell Death-1 Deficiency Exacerbates T Cell Activation and Atherogenesis despite Expansion of Regulatory T Cells in Atherosclerosis-Prone Mice}, series = {PLoS ONE}, volume = {9}, journal = {PLoS ONE}, number = {4}, issn = {1932-6203}, doi = {10.1371/journal.pone.0093280}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119823}, pages = {e93280}, year = {2014}, abstract = {T cell activation represents a double-edged sword in atherogenesis, as it promotes both pro-inflammatory T cell activation and atheroprotective Foxp3(+) regulatory T cell (Treg) responses. Here, we investigated the role of the co-inhibitory receptor programmed cell death-1 (PD-1) in T cell activation and CD4(+) T cell polarization towards pro-atherogenic or atheroprotective responses in mice. Mice deficient for both low density lipoprotein receptor and PD-1 (Ldlr(-/-)Pd1(-/-)) displayed striking increases in systemic CD4(+) and CD8(+) T cell activation after 9 weeks of high fat diet feeding, associated with an expansion of both pro-atherogenic IFNγ-secreting T helper 1 cells and atheroprotective Foxp3+ Tregs. Importantly, PD-1 deficiency did not affect Treg suppressive function in vitro. Notably, PD-1 deficiency exacerbated atherosclerotic lesion growth and entailed a massive infiltration of T cells in atherosclerotic lesions. In addition, aggravated hypercholesterolemia was observed in Ldlr(-/-)Pd1(-/-) mice. In conclusion, we here demonstrate that although disruption of PD-1 signaling enhances both pro- and anti-atherogenic T cell responses in Ldlr(-/-) mice, pro-inflammatory T cell activation prevails and enhances dyslipidemia, vascular inflammation and atherosclerosis.}, 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{JarauschNeuenrothAndagetal.2022, author = {Jarausch, Johannes and Neuenroth, Lisa and Andag, Reiner and Leha, Andreas and Fischer, Andreas and Asif, Abdul R. and Lenz, Christof and Eidizadeh, Abass}, title = {Influence of shear stress, inflammation and BRD4 inhibition on human endothelial cells: a holistic proteomic approach}, series = {Cells}, volume = {11}, journal = {Cells}, number = {19}, issn = {2073-4409}, doi = {10.3390/cells11193086}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-289872}, year = {2022}, abstract = {Atherosclerosis is an important risk factor in the development of cardiovascular diseases. In addition to increased plasma lipid concentrations, irregular/oscillatory shear stress and inflammatory processes trigger atherosclerosis. Inhibitors of the transcription modulatory bromo- and extra-terminal domain (BET) protein family (BETi) could offer a possible therapeutic approach due to their epigenetic mechanism and anti-inflammatory properties. In this study, the influence of laminar shear stress, inflammation and BETi treatment on human endothelial cells was investigated using global protein expression profiling by ion mobility separation-enhanced data independent acquisition mass spectrometry (IMS-DIA-MS). For this purpose, primary human umbilical cord derived vascular endothelial cells were treated with TNFα to mimic inflammation and exposed to laminar shear stress in the presence or absence of the BRD4 inhibitor JQ1. IMS-DIA-MS detected over 4037 proteins expressed in endothelial cells. Inflammation, shear stress and BETi led to pronounced changes in protein expression patterns with JQ1 having the greatest effect. To our knowledge, this is the first proteomics study on primary endothelial cells, which provides an extensive database for the effects of shear stress, inflammation and BETi on the endothelial proteome.}, language = {en} } @phdthesis{Koch2014, author = {Koch, Miriam}, title = {Role of Coagulation Factor XII in Atherosclerosis}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97850}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2014}, abstract = {Atherosclerosis is considered a chronic inflammatory disease of the arterial vessel wall which is not only modulated by innate and adaptive immune responses but also by factors of the blood coagulation system. In general hypercoagulability seems to increase the development and progression of experimental atherosclerosis in mice on an atherogenic background. In addition, the great majority of coagulation proteins including coagulation factor XII (FXII) have been detected in early and advanced human atherosclerotic lesions supporting the cross-link between the coagulation system and atherosclerosis. Moreover, FXII has been detected in close proximity to macrophages, foam cells and smooth muscle cells in these lesions and has been demonstrated to be functionally active in human plaques. Although these data indicate that factor XII may play a role in atherogenesis a direct contribution of FXII to atherogenesis has not been addressed experimentally to date. Furthermore, clinical studies examining the function of FXII in vascular disease have yielded conflicting results. Hence, in order to investigate the function of coagulation factor XII in atherosclerosis apolipoprotein E and FXII-deficient (F12\(^{-/-}\) apoE\(^{-/-}\)) mice were employed. Compared to F12\(^{+/+}\)apoE\(^{-/-}\) controls, atherosclerotic lesion formation was reduced in F12\(^{-/-}\)apoE\(^{-/-}\) mice, associated with diminished systemic T-cell activation and Th1-cell polarization after 12 weeks of high fat diet. Moreover, a significant decrease in plasma levels of complement factor C5a was evidenced in F12\(^{-/-}\)apoE\(^{-/-}\) mice. Interestingly, C5a increased the production of interleukin-12 (IL-12) in dendritic cells (DCs) and enhanced their capacity to trigger antigen-specific interferon-gamma (IFNγ) production in OTII CD4\(^+\) T cells in vitro. Importantly, a reduction in frequencies of IL-12 expressing splenic DCs from atherosclerotic F12\(^{-/-}\)apoE\(^{-/-}\) versus F12\(^{+/+}\)apoE\(^{-/-}\) mice was observed in vivo, accompanied by a diminished splenic Il12 transcript expression and significantly reduced IL-12 serum levels. Consequently, these data reveal FXII to play an important role in atherosclerotic lesion formation and to promote DC-induced and systemic IL 12 expression as well as pro-inflammatory T-cell responses likely at least in part via the activation of the complement system.}, subject = {Gerinnungsfaktor XII}, language = {en} } @article{KraftDrechslerGunrebenetal.2015, author = {Kraft, Peter and Drechsler, Christiane and Gunreben, Ignaz and Heuschmann, Peter Ulrich and Kleinschnitz, Christoph}, title = {Case-control study of platelet glycoprotein receptor Ib and IIb/IIIa expression in patients with acute and chronic cerebrovascular disease}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {3}, doi = {10.1371/journal.pone.0119810}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148806}, pages = {e0119810}, year = {2015}, abstract = {Background Animal models have been instrumental in defining thrombus formation, including the role of platelet surface glycoprotein (GP) receptors, in acute ischemic stroke (AIS). However, the involvement of GP receptors in human ischemic stroke pathophysiology and their utility as biomarkers for ischemic stroke risk and severity requires elucidation. Aims To determine whether platelet GPIb and GPIIb/IIIa receptors are differentially expressed in patients with AIS and chronic cerebrovascular disease (CCD) compared with healthy volunteers (HV) and to identify predictors of GPIb and GPIIb/IIIa expression. Methods This was a case-control study of 116 patients with AIS or transient ischemic attack (TIA), 117 patients with CCD, and 104 HV who were enrolled at our University hospital from 2010 to 2013. Blood sampling was performed once in the CCD and HV groups, and at several time points in patients with AIS or TIA. Linear regression and analysis of variance were used to analyze correlations between platelet GPIb and GPIIb/IIIa receptor numbers and demographic and clinical parameters. Results GPIb and GPIIb/IIIa receptor numbers did not significantly differ between the AIS, CCD, and HV groups. GPIb receptor expression level correlated significantly with the magnitude of GPIIb/IIIa receptor expression and the neutrophil count. In contrast, GPIIb/IIIa receptor numbers were not associated with peripheral immune-cell sub-population counts. Creactive protein was an independent predictor of GPIIb/IIIa (not GPIb) receptor numbers. Conclusions Platelet GPIb and GPIIb/IIIa receptor numbers did not distinguish between patient or control groups in this study, negating their potential use as a biomarker for predicting stroke risk.}, language = {en} } @phdthesis{Michalska2013, author = {Michalska, Marta}, title = {Molecular Imaging of atherosclerosis}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-73243}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Atherosklerose ist eine aktive und progressive Erkrankung, bei der vaskul{\"a}re Adh{\"a}sionsmolek{\"u}le wie VCAM-1 eine entscheidende Rolle durch Steuerung der Rekrutierung von Immunzellen in den fr{\"u}hen und fortgeschrittenen Plaques spielen. Ein zielgerichteter Einsatz von VCAM-1-Molek{\"u}len mit spezifischen Kontrastmitteln ist daher eine M{\"o}glichkeit, die VCAM-1-Expression zu kontrollieren, Plaquewachstum ab einem fr{\"u}hen Zeitpunkt zu visualisieren und eine fr{\"u}he Pr{\"a}vention von Atherosklerose vor Beginn der Thrombusbildung zu etablieren. Des Weiteren bietet die nichtinvasive Magnetresonanz (MR)-Bildgebung den Vorteil der Kombination molekularer und morphologischer Daten. Sie erm{\"o}glicht, mithilfe von entwickelten VCAM-1-markierten Eisenoxidpartikeln, den spezifischen Nachweis entz{\"u}ndlicher Prozesse w{\"a}hrend der Atherosklerose. Diese Arbeit belegt, dass mit dem VCAM-1-Konzept eine vielversprechende Herangehensweise gefunden wurde und dass das, mit spezifischen superparamagnetischen Eisenoxid (USPIO) konjugierte VCAM-1-Peptid, gegen{\"u}ber unspezifischer USPIOs ein erh{\"o}htes Potenzial bei der Untersuchung der Atherosklerose in sich tr{\"a}gt. Im ersten Teil der Arbeit konnte im Mausmodell gezeigt werden, dass gerade das VCAM-1-Molek{\"u}l ein sinnvoller Ansatzpunkt zur Darstellung und Bildgebung von Atherosklerose ist, da in der fr{\"u}hen Phase der Entz{\"u}ndung die vaskul{\"a}ren Zelladh{\"a}sionsmolek{\"u}le {\"u}berexprimiert und auch kontinuierlich, w{\"a}hrend der fortschreitenden Plaquebildung, hochreguliert werden. Weiterhin beschreibt diese Arbeit die Funktionst{\"u}chtigkeit und das Verm{\"o}gen des neu gestalteten USPIO Kontrastmittels mit dem zyklischen Peptid, in seiner Spezialisierung auf die VCAM-1 Erkennung. Experimentelle Studien mit ultra-Hochfeld-MRT erm{\"o}glichten weitere ex vivo und in vivo Nachweise der eingesetzten USPIO-VCAM-1-Partikel innerhalb der Region um die Aortenwurzel in fr{\"u}hen und fortgeschrittenen atherosklerotischen Plaques von 12 und 30 Wochen alten Apolipoprotein E-defizienten (ApoE-/-) M{\"a}usen. Mit ihrer Kombination aus Histologie und Elektronenmikroskopie zeigt diese Studie zum ersten Mal die Verteilung von VCAM-1-markierten USPIO Partikeln nicht nur in luminalem Bereich der Plaques, sondern auch in tieferen Bereichen der medialen Muskelzellen. Dieser spezifische und sensitive Nachweis der fr{\"u}hen und fortgeschrittenen Stadien der Plaquebildung bringt auf molekularer Ebene neue M{\"o}glichkeiten zur Fr{\"u}herkennung von atherosklerotischen Plaques vor dem Entstehen von 8 Rupturen. Im Gegensatz zum USPIO-VCAM-1-Kontrastmittel scheiterten unspezifische USPIO Partikel an der Identifikation fr{\"u}her Plaqueformen und begrenzten die Visualisierung von Atherosklerose auf fortgeschrittene Stadien in ApoE-/- M{\"a}usen.}, subject = {VCAM}, language = {en} } @phdthesis{Padmapriya2008, author = {Padmapriya, Ponnuswamy}, title = {Insight into oxidative stress mediated by nitric oxide synthase (NOS) isoforms in atherosclerosis}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-30659}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2008}, abstract = {The principle product of each NOS is nitric oxide. However, under conditions of substrate and cofactor deficiency the enzymes directly catalyze superoxide formation. Considering this alternative chemistry of each NOS, the effects of each single enzyme on key events of atherosclerosis are difficult to predict. Here, we evaluate nitric oxide and superoxide production by all three NOS isoforms in atherosclerosis. ESR measurements of circulating and vascular wall nitric oxide production showed significantly reduced nitric oxide levels in apoE/eNOS double knockout (dko) and apoE/iNOS dko animals but not in apoE/nNOS dko animals suggesting that eNOS and iNOS majorly contribute to vascular nitric oxide production in atherosclerosis. Pharmacological inhibition and genetic deletion of eNOS and iNOS reduced vascular superoxide production suggesting that eNOS and iNOS are uncoupled in atherosclerotic vessels. Though genetic deletion of nNOS did not alter superoxide production, acute inhibition of nNOS showed that nNOS contributes significantly to superoxide production. In conclusion, uncoupling of eNOS occurs in apoE ko atherosclerosis but eNOS mediated superoxide production does not outweigh the protective effects of eNOS mediated nitric oxide production. We show that although nNOS is not a major contributor of the vascular nitric oxide formation, it prevents atherosclerosis development. Acute inhibition of nNOS showed a significant reduction of superoxide formation suggesting that nNOS is uncoupled. The exact mechanism of action of nNOS in atheroprotection is yet to be elucidated. Genetic deletion of iNOS reduced NADPH oxidase activity. Thus, iNOS has both direct and indirect proatherosclerotic effects, as it directly generates both nitric oxide and superoxide simultaneously resulting in peroxynitrite formation and indirectly modulates NADPH oxidase activity. We hypothesize that eNOS is coupled in the disease free regions of the vessel and contributes to nitric oxide generation whereas in the diseased region of the vessel it is uncoupled to produce superoxide (Figure 16). nNOS expressed in the smooth muscle cells of the plaque contributes to the local superoxide generation. iNOS expressed in smooth muscle cells and leukocytes of the plaque generates superoxide and nitric oxide simultaneously to produce the strong oxidant peroxynitrite.}, subject = {atherosclerosis}, language = {en} } @phdthesis{Parczyk2010, author = {Parczyk, Marco}, title = {In vivo NMR-methods to study effects of atherosclerosis in mice}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-53302}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2010}, abstract = {Background Transgenic mouse models are increasingly used to study the pathophysiology of human cardiovascular diseases. The aortic pulse wave velocity (PWV) is an indirect measure for vascular stiffness and a marker for cardiovascular risk. Results This work presents three MR-methods that allow the determination of the PWV in the descending murine aorta by analyzing blood flow waveforms, arterial distension waveforms, and a method that uses the combination of flow and distension waveforms. Systolic flow pulses were recorded with a temporal resolution of 1 ms applying phase velocity encoding. In a first step, the MR methods were validated by pressure waveform measurements on pulsatile elastic vessel phantoms. In a second step, the MR methods were applied to measure PWVs in a group of five eight-month-old apolipoprotein E deficient (ApoE(-/-)) mice and an age matched group of four C57Bl/6J mice. The ApoE(-/-) group had a higher mean PWV than the C57Bl/6J group. Depending on the measurement technique, the differences were or were not statistically significant. Conclusions The findings of this study demonstrate that high field MRI is applicable to non-invasively determine and distinguish PWVs in the arterial system of healthy and diseased groups of mice.}, subject = {Arteriosklerose}, language = {en} } @article{PaudelFusiSchmidt2021, author = {Paudel, Rupesh and Fusi, Lorenza and Schmidt, Marc}, title = {The MEK5/ERK5 pathway in health and disease}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {14}, issn = {1422-0067}, doi = {10.3390/ijms22147594}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-261638}, year = {2021}, abstract = {The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway.}, 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{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{WinterAndelovicKampfetal.2021, author = {Winter, Patrick M. and Andelovic, Kristina and Kampf, Thomas and Hansmann, Jan and Jakob, Peter Michael and Bauer, Wolfgang Rudolf and Zernecke, Alma and Herold, Volker}, title = {Simultaneous measurements of 3D wall shear stress and pulse wave velocity in the murine aortic arch}, series = {Journal of Cardiovascular Magnetic Resonance}, volume = {23}, journal = {Journal of Cardiovascular Magnetic Resonance}, number = {1}, doi = {10.1186/s12968-021-00725-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259152}, pages = {34}, year = {2021}, abstract = {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.}, language = {en} } @article{YurdadoganMalschKotsevaetal.2021, author = {Yurdadogan, Tino and Malsch, Carolin and Kotseva, Kornelia and Wood, David and Leyh, Rainer and Ertl, Georg and Karmann, Wolfgang and M{\"u}ller-Scholden, Lara and Morbach, Caroline and Breuning, Margret and Wagner, Martin and Gelbrich, G{\"o}tz and Bots, Michiel L. and Heuschmann, Peter U. and St{\"o}rk, Stefan}, title = {Functional versus morphological assessment of vascular age in patients with coronary heart disease}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-021-96998-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265810}, year = {2021}, abstract = {Communicating cardiovascular risk based on individual vascular age (VA) is a well acknowledged concept in patient education and disease prevention. VA may be derived functionally, e.g. by measurement of pulse wave velocity (PWV), or morphologically, e.g. by assessment of carotid intima-media thickness (cIMT). The purpose of this study was to investigate whether both approaches produce similar results. Within the context of the German subset of the EUROASPIRE IV survey, 501 patients with coronary heart disease underwent (a) oscillometric PWV measurement at the aortic, carotid-femoral and brachial-ankle site (PWVao, PWVcf, PWVba) and derivation of the aortic augmentation index (AIao); (b) bilateral cIMT assessment by high-resolution ultrasound at three sites (common, bulb, internal). Respective VA was calculated using published equations. According to VA derived from PWV, most patients exhibited values below chronological age indicating a counterintuitive healthier-than-anticipated vascular status: for VA(PWVao) in 68\% of patients; for VA\(_{AIao}\) in 52\% of patients. By contrast, VA derived from cIMT delivered opposite results: e.g. according to VA\(_{total-cIMT}\) accelerated vascular aging in 75\% of patients. To strengthen the concept of VA, further efforts are needed to better standardise the current approaches to estimate VA and, thereby, to improve comparability and clinical utility.}, language = {en} }