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Maren Depke Results Liver Gene Expression Pattern in a Mouse Psychological Stress Model molecule Nnmt was up-regulated selectively after repeated stress. To verify the biological relevance of an altered redox homeostasis, protein carbonylation was analyzed as a marker of oxidative stress. Remarkably, increased protein carbonyl content of plasmatic and hepatic proteins was detectable already immediately after acute stress, indicating a rapid and significant protein damage by increased formation of reactive oxygen species (data not shown). After chronic psychological stress the protein-carbonyl content had returned to the level seen in nonstressed control mice (data not shown). Finally, the expression of Glrx (glutaredoxin) and Gsta (glutathione S-transferase) was significantly increased in the liver of chronically stressed mice indicating that compensatory antioxidative mechanisms were induced. This may explain why the carbonyl content of proteins in plasma and liver in repeatedly stressed mice had declined to the normal level observed in nonstressed control mice (data not shown). Repeated stress-induced apoptosis in the liver Several genes that were regulated in the liver of repeatedly stressed mice provided hints for increased cell death. By comparing the mRNA profile of liver homogenates of acutely and repeatedly stressed mice a highly similar pattern of altered gene expression of cell cycle and apoptosis-related genes was observed. In both acutely and chronically stressed animals, increased mRNA levels compared to non-stressed controls were detected for Tnfrsf1b, Cdkn1a, Cebpb, Igfbp1, and Gadd45b (Fig. R.1.8 A). Other genes, such as Fos and Jun, which were induced immediately after acute stress exposure, did not reveal prolonged high mRNA expression (Fig. R.1.8 A, B), whereas yet another group, including Ccnd1 and Xbp1, were selectively repressed after the ninth stress session (Fig. R.1.8 B). Using TUNEL techniques, induction of hepatocyte apoptosis was not detectable immediately after one single acute stress exposure (Fig. R.1.8 D), but high numbers of dead cells in livers after repeated stress exposure (Fig. R.1.8 E) compared with control mice (Fig. R.1.8 C) were documented. However, the liver mass after the ninth stress session was only slightly decreased compared to non-stressed control animals (Fig. R.1.8 F). This may be caused by induction of repair processes for which heightened hepatic expression of IL-6 receptor and Ptp4a1 after chronic stress are indications. Fig. R.1.8. Differential regulation of cell death associated genes in liver of stressed mice. Genes resulting from a search for “apoptosis AND liver”, “apoptosis AND hepatocyte”, “cell death AND liver” and “cell death AND hepatocyte” using Ingenuity Pathway Analysis (IPA, Ingenuity Systems, www.ingenuity.com) were collected in a list. All genes of this list which displayed differential regulation in liver after acute and/or chronic stress exposure were added to a new user-defined pathway as analysis nodes and interactions between these selected genes were drawn using the “Connect” tool of IPA. Edge lines that are continuous represent direct interactions, whereas broken lines indicate indirect influences. The pathway was overlaid with expression data from (A) acute stress and from (B) chronic stress. Red indicates increased and green decreased expression after stress exposure compared with the control. Intensity of the node color represents the degree of up (red) and down (green) regulation in the stressed livers. Different shapes of the nodes indicate the functional classes of the gene products (e. g. vertical ellipse − transmembrane receptor; horizontal ellipse − transcription regulator; vertical rectangle − G-protein coupled receptor; horizontal rectangle − ligand-dependent nuclear receptor; trapezium − transporter; triangle − phosphatase; inverted triangle − kinase; vertical rhomb − enzyme; horizontal rhomb − peptidase; quadrat − cytokine; double lined circle − group or complex; single lined circle − other). The level of apoptosis TUNEL assay (x400): compared to the control (C), livers of mice exposed to acute stress did no display any significant increase in the level of apoptosis (D). However, high numbers of apoptotic hepatocytes were detected in repeatedly stressed mice (E). Each picture is representative for n = 9 mice/group. Increased apoptosis did not alter liver mass (F), even after the 9th stress cycle (black box plots) compared with non-stressed mice (white box plots) n = 9 mice/group; data representative for least 2 independent experiments. 72
liver weight [g] Maren Depke Results Liver Gene Expression Pattern in a Mouse Psychological Stress Model A C D B E F 1.4 1.2 1 0.8 0.6 73
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G E N O M E W I D E C H A R A C T E
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Maren Depke C O N T E N T S GENOMEW
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Maren Depke Z U S A M M E N F A S S
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Maren Depke Zusammenfassung der Dis
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Maren Depke S U M M A R Y O F D I S
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Maren Depke Summary of Dissertation
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Maren Depke I N T R O D U C T I O N
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Maren Depke Introduction Besides op
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Maren Depke Introduction Extracellu
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Maren Depke Introduction with heigh
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Maren Depke Results Host Cell Gene
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Maren Depke Results Pathogen Gene E
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S. aureus RN1HG sample conditions a
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mean normalized intensity mean norm
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mean normalized intensity Maren Dep
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log 2 (ratio) log 2 (ratio) log 2 (
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Maren Depke D I S C U S S I O N A N
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Maren Depke Discussion and Conclusi
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Maren Depke References Athanasopoul
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Maren Depke References Byrne GI, Le
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Maren Depke References Demling R. T
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Maren Depke References Foss GS, Pry
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Maren Depke References Hagopian K,
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Maren Depke References Jin T, Bokar
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Maren Depke References Kwan T, Liu
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Maren Depke References Luster AD, U
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Maren Depke References Namiki S, Na
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Maren Depke References Puccetti P.
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Maren Depke References Siewert E, B
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Maren Depke References van den Akke
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Maren Depke References Yang XL, Sch
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Maren Depke A F F I D A V I T / E R
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Maren Depke Acknowledgments Kidney
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