The role of IκBζ and IκBNS in psoriasis and immune cell activation

Psoriasis is a chronic autoimmune skin disease that affects approximately 2% of the people worldwide, therefore reduces quality of life of the affected persons. In addition, it is often associated with comorbidities, such as arthritis, enhanced risk for cardiovascular diseases, diabetes or metabolic syndromes. This inflammatory disease is characterized by keratinocyte hyperproliferation and a massive infiltration of neutrophils, macrophages, and T cells, which is triggered by environmental factors like incisions in genetically predisposed individuals. The transcription factor NF-κB is assumed to be an essential mediator in the pathogenesis of psoriasis, since in lesional psoriatic skin enhanced levels of activated, phosphorylated NF-κB dimers were observed. The action of the NF-κB heterodimer itself is regulated via IκB proteins such as IκBζ and IκBNS, which are localized in the nucleus where they modulate the transcription of NF-κB-dependent target genes. Especially IκBζ is in central focus in the scientific community, since its encoding gene NFKBIZ is overexpressed in human psoriatic lesions, whereas its global genetic depletion protects against psoriasis progression in different psoriasis-like mouse models. Although IκBζ has emerged as a novel regulator for pathogenesis of psoriasis, it remains unclear whether IκBζ expression in keratinocytes or CD4+ immune cells is relevant for its pathogenic effects. Moreover, the contribution of IκBNS to psoriasis progression is unknown. In order to address these questions, we generated keratinocyte- as well as CD4-specific IκBζ-deficient mice and performed imiquimod-triggered psoriasis mouse models. Our results demonstrate that KC-derived IκBζ drives psoriasis development and associated systemic inflammation, whereas IκBζ expressed by CD4+ cells plays a minor role in driving skin inflammation, since abrogated IL-17/TNFα signaling in CD4+ IκBζ KO alone is not sufficient to block psoriasis progression. IL-17 induces important pathogenetic factors of psoriasis such as antimicrobial peptides, epidermal hyperproliferation and neutrophil recruitment, thus blockade of this pathway is considered a therapeutic approach. To strengthen these observations, we additionally performed IL-36- and IL-23-driven models in KC-specific knockout mice. Absence of IκBζ in keratinocytes led to suppressed psoriasis-associated gene expression (especially immune cell recruitment and pro-inflammatory cytokines) and protection against typical pathogenic effects. The role of another IκB member was also investigated in this thesis, since an effect on the development of psoriasis was suspected for IκBNS as well. However, initial results demonstrated that IMQ-induced psoriasis-like skin inflammation is unaffected by global IκBNS depletion, therefore a minor contribution of this atypical inhibitor can be suggested in psoriasis disease. Furthermore, the impact of IκBNS in dendritic cell differentiation and functionality was under explored. Our results demonstrated that IκBNS suppresses differentiation as well as functionality of dendritic cells in several in vitro models. Additionally, we were able to show initial data that MHC class II activation is blocked by IκBNS via CIITA inhibition. Taken together, these results provide insight into the contribution of IκBζ and IκBNS in psoriasis and immune cell activation; esp. the contribution of KC-derived IκBζ in dermatitis protection, which in turn uncovers a pivotal role as key mediator of psoriasis.Die Dissertation ist gesperrt bis zum 25. Juni 2026

Der Körper spricht. Zur Diskursivierung der Rhetorik des Körpers in der Antike

Die Dissertation ist gesperrt bis zum 19. Juli 2026

Regulators Influencing the Heterologous Production of Liponucleoside Antibiotics in Streptomyces coelicolor M512

Dissertation gesperrt bis zum 17.05.2026!Die heterologe Expression von Biosynthese-Genclustern ist ein häufig angewandtes Vorgehen in der Naturstoffforschung und erleichtert Untersuchungen der involvierten Gene an der Biosynthese des resultierenden Naturstoffs, sowie die Entwicklung möglicher Strategien zur Produktionssteigerung. Die Auswirkungen globaler Regulatoren des Wirtsstammes auf die Expression eingebrachter Gencluster, sowie die Anpassungen im Stoffwechsel des Wirtsstammes finden jedoch größtenteils kaum Beachtung. Eine vorangegangene Studie deutete auf ein regulatorisches Zusammenspiel zwischen der heterologen Expression der Biosynthesegene von Novobiocin auf der einen Seite, und der Bereitstellung von biosynthetischen Vorstufen aus dem Primärmetabolismus des Wirtes auf der anderen Seite hin. Ziel der vorliegenden Arbeit war es daher, Regulatoren des heterologen Wirtes, Streptomyces coelicolor M512, zu identifizieren, die mit den eingebrachten Genclustern für die beiden Liponucleosid-Antibiotika Caprazamycin und Liposidomycin interagieren und deren Produktion beeinflussen. Liposidomycine und Caprazamycine werden von verschiedenen Streptomyces Stämmen produziert und wurden Mitte der 1980er bzw. Anfang der 2000er Jahre entdeckt. Beide Liponucleosid-Antibiotika zeigen eine gute Bioaktivität gegen Mykobakterien, bedingt durch ihre ausgeprägten chemisch strukturellen Ähnlichkeiten. Dementsprechend ähneln sich ihre Biosynthesewege, die auf den gleichen biosynthetischen Vorstufen beruhen, sowie die genetische Organisation der entsprechenden Gencluster, die untereinander eine sehr hohe Sequenzhomologie aufweisen. Somit wurde für die heterologen Stämme S. coelicolor M512, mit vollständigem Caprazamycin (cpzLK09) oder Liposidomycin (lpmLK01) Gencluster, auch ein vergleichbares Zusammenspiel zwischen Regulatoren des Wirtes und Promoter-Regionen der eingebrachten Gencluster vermutet. In dieser Arbeit wurden DNA-affinity-capturing assays mit nachfolgender Massenspektrometrie genutzt, um Regulatoren des Wirtsstammes zu identifizieren, die an ausgewählte intergene Bereiche des Caprazamycin- und Liposidomycin-Genclusters binden. Die untersuchten intergenen Bereiche wurden als Promotor-Regionen mittels RNA-Sequenzierung verifiziert. Als Negativkontrolle diente die Promotor-Region des vegetativen Sigma Faktors hrdB, um die Bindungsspezifität beurteilen zu können. Insgesamt wurden jeweils 1906 und 1540 Proteine an den Promotor-Regionen der Gencluster aus S. coelicolor M512/cpzLK09 und S. coelicolor M512/lpmLK01 identifiziert. Von diesen banden nur drei Proteine spezifisch an zueinander gehörige Promotor-Regionen aus beiden Genclustern, was auf Unterschiede hinsichtlich der regulatorischen Wechselwirkung mit dem Wirtsstamm hindeutete. Basierend auf einer spezifischen Bindung, oder aber einer bereits bekannten Beteiligung an der Regulation zur Bereitstellung von Vorläufermolekülen, wurden fünf mutmaßliche Regulatoren für eine weitere Charakterisierung ausgewählt. Von diesen führte die Überexpression von zwei Genen zu signifikant erhöhter Caprazamycin Produktion. Die Überexpression eines cAMP-Rezeptor Proteins, ein Regulator des Leucin-Isovalerat-Abbauwegs, der Vorstufen für die Liponucleosid-Biosynthese bereitstellt, erhöhte die Caprazamycin und Liposidomycin Produktionsmengen signifikant. Der zweite Regulator, der die heterologe Caprazamycin-Produktion beeinflusste, gehört zur Familie der TetR Regulatoren. Obwohl dieses Protein im DNA-affinity-capturing assay spezifisch an einer zueinander korrespondierenden Promotor-Region in beiden Genclustern gebunden hatte, steigerte dessen Gen-Überexpression nur die Caprazamycin- und nicht die Liposidomycin-Produktion. Deshalb wurde die Bindestelle des Regulators in den Promotor-Regionen durch Biolayer-interferometry Messungen genauer bestimmt. Die Positionen der primären Bindestelle sind interessanterweise in beiden Genclustern unterschiedlich: während der TetR-Typ Regulator in der ausgewählten Region des Caprazamycin Genclusters im codierenden Bereich des Strang-aufwärts liegenden Gens cpz9 bindet, bindet er in der Mitte der intergenen Region zwischen lpmG und lpmH aus dem Liposidomycin Gencluster. Dies könnte die unterschiedlichen Effekte auf die Liponucleosid Produktion in beiden heterologen Stämmen erklären. Zusätzlich bot die Identifikation der Bindestellen die Möglichkeit, eine Konsensus-Erkennungssequenz zu bestimmen, die experimentell ebenfalls mit Biolayer-interferometry verifiziert wurde. Eine Genom-weite Suche nach möglichen regulatorischen Zielsequenzen in S. coelicolor mit Hilfe der Konsensus-Sequenz, erbrachte jedoch keine offensichtliche Verbindung zur Liponucleosid Biosynthese oder deren Vorläufermolekülen. Im letzten Teil dieser Arbeit wurde der Fokus auf die Charakterisierung der Cluster-spezifischen Regulatoren des Caprazamycin und Liposidomycin Biosynthese-Genclusters, Cpz9 und LpmG, gelegt. Dafür wurden die entsprechenden Gene, die vermutlich für AraC-ähnliche Aktivatoren codieren, einzeln in den heterologen Produzentenstämmen überexprimiert. Während die cpz9 Überexpression in S. coelicolor M512/cpzLK09 nur eine leichte Erhöhung der Produktivität von Caprazamycinen erbrachte, führte die Überexpression von lpmG in S. coelicolor M512/lpmLK01 zu einer starken, signifikanten Überproduktion von Liposidomycinen. Hierdurch konnte die geringe Expression von lpmG als möglicher limitierender Faktor für die Liposidomycin Produktion im heterologen Expressionsstamm identifiziert werden

Investigating the use of mycophenolic acid for the treatment of Retinitis Pigmentosa

Purpose: Retinitis pigmentosa is a degenerative genetic disorder in which pho- toreceptor cell death can be connected to high cGMP levels. This is exemplified by the rd1 mouse model where a mutation in the Pde6b gene leads to decreased cGMP hydrolysis in photoreceptors. While the enzyme guanylyl cyclase (GC) synthesizes cGMP in photoreceptors, inosine monophosphate dehydrogenase-1 (IMPDH1) catalyzes the rate-limiting step in the biosynthesis leading up to cGMP. Hence, inhibiting IMPDH1 may be a strategy for the reduction of photoreceptor cGMP levels and cell death. I explored the capacity of the registered immunosup- pressive drug mycophenolic acid (MPA) to reduce photoreceptor cGMP levels and cell death in rd1 retinal explant cultures. Methods: The retinal expression patterns of IMPDH1 and GC were assessed in wild-type and rd1 mouse retina using immunofluorescence. Organotypic retinal explant cultures derived from post-natal day (P) 5 rd1 mice were treated with MPA in six different concentrations ranging from 1 to 1000 μM. Parallel control cultures received vehicle or medium only. The retinal explants were cultured from P5 to P11 with medium changes every two days. At P11, the explants were fixed in paraformaldehyde, cryosectioned, and stained for cell death using the TUNEL- assay. TUNEL-positive cells were counted and compared with controls. To de- termine treatment effects on cone photoreceptors, these were quantified using PNA labelling. Results: IMPDH1 was expressed in photoreceptor inner segments, outer plexi- form layer, neurites in the outer nuclear layer, and cell bodies in the inner nuclear layer. GC staining labelled the outer segments of photoreceptors. In rd1 ex vivo explant cultures treated with MPA, cell death decreased in a concentration-de- pendent manner. Between 40 and 250 μM cell death was significantly reduced, while at 1000 μM cell death was strongly increased, and retinal structure was lost. No significant differences in cone cell numbers were found by PNA staining. Conclusion: The localization of IMPDH1 expression to photoreceptor inner seg- ments makes it a potentially druggable target for the treatment of retinitis pigmen- tosa. Importantly, the treatment with MPA revealed a neuroprotective effect in a concentration range achievable in a clinical setting.Dissertation ist gesperrt bis 31. März 2026

Myofibroblast Specific cGMP/cGKI Signaling Counteracts Ang II-Induced Cardiac Remodeling

The present work focused on the investigation of the putative role of the cGMP-dependent protein kinase I (cGKI) in Postn+ cardiac myofibroblasts (CMFs) in mediating the well-known antifibrotic actions of the NO/cGMP and NP/cGMP signaling cascade(s). To address this question, we generated mice with a specific deletion of cGKI in CMFs (cmfKO) and corresponding littermate control animals (CTR) by using a transgenic PostniCreTg/+ mouse line expressing the tamoxifen (TAM)-inducible Cre recombinase controlled by the Postn-Promotor (Kaur et al., 2016). To induce cardiac remodeling, osmotic minipumps releasing angiotensin II (Ang II) over 28 days were implanted subcutaneously. CMF-specific Cre-recombination resulted in a pronounced reduction of cGKI expression levels in fibrotic heart areas as well as in primary cardiac fibroblasts (CF)/CMF cell cultures derived from TAM and Ang II-treated cmfKO mice. Interestingly, although both genotypes responded identically to Ang II in terms of blood pressure and heart weight, cmfKO mice exhibited a slightly increased myocardial vulnerability compared to Ang II-treated CTR animals. In line with this adverse outcome, Ang II challenged cmfKO mice displayed a significantly increased collagen deposition as well as cardiomyocyte (CM) cross sectional areas and cell death versus corresponding CTR animals. Furthermore, cmfKO mice showed a structure-related decline in global cardiac performance (%EF, %FS) and muscle deformation capacity following prolonged Ang II stimulation compared to corresponding CTR mice. Consistent with the observed phenotype in vivo, primary CF/CMFs isolated from Ang II-treated cmfKO mice exhibited accelerated proliferation behavior compared with CTR-derived CF/CMFs. Future studies are still required to address how cGKI contributes to further CMF characteristics including ECM-production and migration. Overall, the present work provides evidence for a cardioprotective role of the cGMP/cGKI cascade in CMF during Ang II-mediated cardiac remodeling, with these antifibrotic effects attributable to tight regulation of CMF expansion.Die Dissertation ist gesperrt bis zum 12. Januar 2026

Swe1/Wee1 Regulates a Novel G2 Nutrient Response Mechanism in Saccharomyces Cerevisiae

Die Dissertation ist gesperrt bis zum 31. Dezember 2026 !Saccharomyces cerevisiae requires nutrients as fuel and also as signaling molecules to drive growth and the cell division cycle. Nutrient signaling is critical for the decision to enter the cell cycle at the G1 commitment point START. However, how post START cells respond to nutrient signaling during the S/G2/M phases of the cell cycle is poorly understood. Here, I investigate the crosstalk between metabolism and the S G2 M cell cycle with focus on the G2/M transition. I use fluorescence microscopy to analyze single cells growing in a microfluidic cultivation platform with controlled nutrient supply. In this set up, I analyze the yeast cells' response to complete glucose removal in different cell cycle phases. For example, I examine the G2/M transition by quantifying G2 specific regulators of the cyclin dependent kinase (CDK1): B type cyclin Clb2, the inhibitory kinase Swe1 (Wee1), and its counteracting phosphatase Mih1 (Cdc25). This study shows that cells can respond to nutrient depletion in all cell cycle phases. Starved cells frequently arrest in (S )G2, but also M phase. Surprisingly, I found arrests in late G2 phase with high levels of the major mitotic promoter: nuclear CDK Clb2. Using different mutants and novel fluorescent reporters, I found that complete glucose removal leads to Swe1 transport into the nucleus, where Swe1 inactivates and thus also stabilizes CDK Clb2. This restriction of nuclear CDK activity enables high Clb2 arrests in G2 phase. Deleting swe1 causes premature mitotic entry and more unregulated arrests in glucose starved cells. The Swe1 reporter is stabilized in the nucleus of wild type (WT) cells even under prolonged starvation, whereas Δswe1 cells rapidly degrade it after starvation entry. I conclude that the Swe1 – CDK Clb2 negative feedback loop but also the Swe1 – Mih1 balance are key regulators to enable and maintain cell cycle arrests in G2 phase. I propose a novel starvation response mechanism that links complete glucose removal to suppression of CDK activity in order to arrest cells in (S )G2 phase. My results provide evidence for a mechanism that relies on the Swe1 dependent phosphorylation of CDK Clb2 and further that this response is independent of the established Bud Morphogenesis Checkpoint. I thus speculate that the novel starvation response mechanism constitutes a previously undescribed G2 nutrient checkpoint, restricting mitotic entry to favorable nutrient conditions

The Role of Temporal Cortex and Superior Colliculus in Attention Networks: A Human and Macaque Comparison

The significance of temporal cortex areas in attention control, which has traditionally been neglected in conventional attention research, has gained prominent attention thanks to the efforts of numerous research groups. The concept of a temporal attention network has been increasingly supported by a growing body of evidence, lending more credence to its existence. In particular, the significance of the fundus of the superior temporal sulcus (FST) and the posterior inferotemporal region (PIT) has ignited debates around anatomical and functional homologue between humans and macaques. In our series of projects, we have deconstructed this conversation to provide clarifying insights that go beyond semantics, unveiling distinct functional dynamics of these regions. In the first project, we detected occipito-temporal areas activations in concomitance to a covert attentional task, consistent with cortical areas at the posterior portion of the temporal cortex reported in other recent studies. Furthermore, we identified task-related activations in the Superior Colliculus (SC), in addition to evidence in favour of somatosensory-driven activations in the deep layers of the SC. In the second project we investigated stimulus-independent attentional effects in the human FST and surrounding temporal areas in response to a covert attentional task. We found strong lateralization of attention-related signals in FST, PIT and neighboring areas for motion and white noise stimuli. We observed significant activations related to attentional shifts to the contralateral visual field in the Superior Colliculus, and a significant effect for motion but not for white noise stimuli for the ‘attend vs ignore’ contrast. These results detail temporal nodes of attention that were largely unnoticed in earlier studies on covert shifts of visual attention in humans. In the third project we provided evidence supporting the idea that FST is a functionally homologous area in monkey and humans. We described its connectivity with critical hubs in the attention control network such as the SC, the frontal eye fields (FEF), and regions of the intraparietal sulcus (IPS) in macaques and confirmed these findings in humans. Moreover, we investigated the functional connectivity of PIT in humans, the second temporal cortex area recently reported to be a key player in human and macaque attention control. We discovered that PIT was also connected to areas which are crucial for attention control, such as FEF, LIP and SC. Finally, we studied which regions of the human brain exhibit stronger connectivity with either one of these areas. We found that FST exhibits stronger connectivity with regions of the dorsal attention network whereas PIT shows stronger connectivity with regions of the ventral attention network. In conclusion, we present evidence suggesting that the FST is functionally homologous in humans and macaques, proposing a resolution on the existing disparity in literature about the counterpart of this region in humans. Furthermore, FST exhibits a unique functional role which makes it distinct from PIT. Both regions in humans have a clear and consistent connections with other well-established cortical attention networks, while in monkeys the frontal and parietal connections are more pronounced for FST. In macaques the FST is strongly connected to the SC, while in humans both FST and PIT are connected to the SC. This supports the notion that this temporal hub for attention control is relatively preserved across species in its subcortical connections, while its cortical connections are more species- specific, with greater divergence in the human brainDie Dissertation ist gesperrt bis zum 26. November 2026

Next-Generation Tetrazine Probes for the Reactivity-Guided Isolation of Isonitrile-Containing Natural Products

Antimicrobial resistance (AMR), the ability of pathogens to withstand treatment with currently used medicines, poses a global threat to the health and welfare of both humans and animals. Since the pipeline for novel antibiotics remains largely underpopulated, the discovery and development of novel antibiotics, ideally with novel mechanisms of action, is crucial to ensuring the treatability of microbial infections in the future. In the past, Natural Products (NPs) have often served as antibiotics or blueprints thereof. Large proportions of the bacterial potential are currently untapped, thus the discovery of novel NPs with antimicrobial activity from bacterial origin remains a promising route to antibiotic candidates. A major drawback is the high rate of re-discovery. Hence, new approaches to NP discovery need to be explored. One approach is chemical activity guided isolation of NPs from complex extracts. Rather than focusing on biological activity, this approach targets specific chemical reactivity. Isonitrile-containing natural products (ICNPs) have been known since the 1950s. Due to their unique electronic configuration, they are known as metal-binders or metallophores. Many ICNPs were shown to function in copper homeostasis (chalkophores). This metal coordinating ability is often strictly correlated to their antibacterial activity, rendering ICNPs ideal candidates as novel antibiotics. In this work, the chemoselective tetrazine-isonitrile click reaction was employed to label and isolate ICNPs from complex bacterial extracts. A series of optimized tetrazine probes for different application scenarios was developed and tested in two bacterial extracts containing ICNPs. The chemoselectivity of a newly developed tetrazine probe was compared to two literature reported isonitrile-labelling probes.Die Dissertation ist gesperrt bis zum 10. November 2026

Organization and functional complex formation within the biosynthetic machinery of glycopeptide antibiotics

Dissertation ist gesperrt bis zum 10. Juli 2026

Pathophysiological and Pharmacological Relevance of NO/cGMP Signaling in Atherosclerosis

Atherosclerosis leads to heart attack and stroke, the most common causes of death worldwide. This disease is characterized by chronic inflammation of the blood vessel walls, accompanied by the formation of atherosclerotic plaques. Vascular smooth muscle cells (VSMCs) play a crucial role in this process. VSMCs significantly contribute to the plaque formation through migration, clonal expansion, and phenotypic modulation. The molecular mechanisms leading to the alteration of VSMC behavior in atherogenesis are not fully understood. The cyclic gua-nosine monophosphate (cGMP) signaling pathway, synthesized by the nitric oxide (NO)-sen-sitive guanylyl cyclase (NO-GC) is a key factor in the (patho-)physiology of VSMCs. It is assumed that a disruption of the NO/cGMP signaling pathway in VSMCs impact phenotypic mod-ulation and plaque growth. However, it remains unclear whether pharmacological stimulation/activation of the NO/cGMP pathway in VSMCs exerts pro- or anti-atherogenic effects. This study aimed to further elucidate the pathophysiological and pharmacological relevance of the NO/cGMP pathway in VSMCs in a mouse model of atherosclerosis and investigate its potential effects on atherosclerotic plaque growth and composition. To modulate the activity of the NO/cGMP signaling pathway in vivo, NO-GC modulating drugs or cell specific genetic in-activation of NO-GC in VSMCs (NO-GCsmko) were used. A novel aspect of this study was the comparison of the effects of a NO-GC activator (BAY Activator) and a NO-GC stimulator (Vericiguat). Both compounds induce cGMP generation by binding to NO-GC but differ in their mode of action. NO-GC stimulators enhance NO-GC activity independently or synergistically with endogenous NO. In contrast, NO-GC activators activate the dysfunctional heme-oxidized NO-GC. Particularly under conditions of increased oxidative stress, as observed in atheroscle-rosis, NO-GC activators are assumed to have high therapeutic potential. Various biochemical, immunological, and histochemical methods were combined for analysis. Initially, the expression of NO-GC as a potential drug target was demonstrated by in situ im-munofluorescence staining in VSMCs and macrophage antigen-2 (MAC2)-positive cells in ath-erosclerotic plaques, indicating the possibility of pharmacological modulation of the enzyme. MAC2 was used as a cellular marker for VSMC-derived transdifferentiated macrophage-like cells or macrophages. Interestingly, en face analysis of atherosclerotic aortas showed that BAY Activator treatment led to a significant increase in the atherosclerotic lesion area, while Vericiguat did not exhibit this pro-atherosclerotic effect. Comprehensive analyses revealed that the administered drugs were detectable in the blood plasma and that various parameters that could influence atherosclerosis, such as blood pressure, plasma lipid profile and complete blood count, were not significantly changed by the BAY Activator treatment. To investigate the functional relevance of the NO/cGMP signaling pathway in VSMCs for the pro-atherosclerotic effect of the BAY Activator, in vitro experiments were performed with primary VSMCs isolated from mouse aortas. First, the effects of NO-GC modulators on intracellular cGMP concentration were visualized in real-time under normal and oxidative conditions using a Förster/fluorescence resonance energy transfer (FRET)-based cGMP biosensor. Additionally, the effects on VSMC growth were examined using the xCELLigence system. These experiments demon-strated that both the BAY Activator and Vericiguat increased cGMP levels and promoted VSMC growth. As expected, the BAY Activator showed higher efficacy in increasing intracellular cGMP levels under conditions of oxidative stress, which may also imply an enhanced efficacy under atherosclerotic conditions. Based on the results of the present study and the existing literature, we postulate that the growth-promoting effects of NO-GC modulators are likely as-sociated with the role of NO-GC in the phenotypic modulation of VSMCs. Interestingly, our in vivo study revealed that the increased atherosclerotic lesion area caused by the BAY Activator treatment was accompanied by an accumulation of MAC2-positive cells. This indicates that activation of the NO/cGMP signaling pathway led to an enrichment of VSMC-derived transdifferentiated macrophage-like cells or macrophages. It was also planned to validate the target specificity of the effects of NO-GC modulators and the pathophysiological role of the NO/cGMP signaling cascade in VSMCs using an NO-GCsmko mouse model. Although we successfully generated the NO-GCsmko mouse model, the preliminary data suggested that the induction of NO-GCsmko led to a hypertensive phenotype and elevated plasma lipid levels, which complicated the interpretation of the data regarding the effects on atherosclerosis. Thus, no further conclusions were drawn from these data at this time. In summary, our results suggest a pro-atherosclerotic effect of activation of the NO/cGMP sig-naling pathway by BAY Activator treatment. We hypothesize that this is closely related to the increased efficacy of BAY Activator under the oxidative conditions prevalent in atherosclerotic plaques and the impact on the phenotypic modulation of VSMCs in the plaque. These findings provide the basis for further research to deepen our understanding of the pathophysiological and pharmacological relevance of the NO/cGMP signaling pathway in atherosclerosis.Die Dissertation ist gesperrt bis zum 11. April 2026