Rapid rearing of dairy heifers during late prepuberty has been linked to impairments in mammary development and reductions in milk yield. Our objective was to determine how varying energy intakes between 2 and 14 wk of age affect mammary parenchymal development. At 2 wk of age, Holstein calves were assigned to 1 of 4 treatments (HH, HL, LH, and LL) with 2 levels of energy intake (High or Low) and 2 periods of growth (2 to 8 and 8 to 14 wk of age). At 14 wk, parenchyma at the stromal interface, mid-gland, and above the cistern were collected, fixed, and embedded in paraffin. Digital images of stained sections were used to determine tissue composition (% epithelium, lumen, and stroma). Immunochemistry revealed estrogen receptor (ER) and Ki67 (nuclear proliferation antigen) positive cells, type IV collagen, fibronectin (FN), and laminin. Images representing 4 increasing grades were used to quantify ECM protein deposition. Lumenal and stromal areas were 3.5 ± 1.4% higher (p<0.01) and 4.0 ± 1.7% lower (p<0.01), respectively, in HH and HL heifers. Ki67 labeling in terminal ductular units and subtending ducts was 2.1 ± 0.8% (p<0.01) and 1.4 ± 0.7% (p<0.05) lower for the same feeding level combination. FN deposition was also increased (p<0.05) in HH and HL heifers. High rates of gain between 2 and 14 wk of age resulted in greater lumenal area and reduced cell proliferation in mammary parenchyma at 14 wk of age. Changes in FN deposition could have mediated growth differences. / Master of Science

ER+ breast cancer raises a significant diagnostic challenge since resistance invariably develops to the current endocrine therapies. 70% of breast cancers are ER+, which results from the overexpression of estrogen receptor. ER mediates strong anti-inflammatory signaling in ER+ tissues. Once activated with estradiol (E2), ER inhibits inflammatory gene expression via protein-protein interactions that block NF-kappa B transcriptional activity. Importantly, NF-kappa B is a primary mediator of resistance in many cancers, including breast cancer. All current endocrine suppressive treatments block this palliative signaling pathway, along with the desired proliferative pathway. Thus, there is a significant unmet clinical need for novel endocrine treatments for breast cancer that can ameliorate patient outcome in resistant populations, be less prone to resistance development, retain anti-inflammatory action, and cause fewer side effects. Following the hypothesis driven approach, the work described here introduces structural analogs of an innovative ligand scaffold, 5,6-bis-(4-hydroxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonic acid phenyl ester, termed OBHS, which reduces gene activation through ligand-induced shifts in helices 8 and 11, thereby indirectly modulating helix 12 of ER (hence, indirect antagonists). This new class of ligands with a bicyclic hydrophobic core retains strong anti-inflammatory effects while dialing out the proliferative effects of E2 (similar to Selective Estrogen Receptor Modulators, SERMS), and could potentially replace the current endocrine therapies of breast cancer. In this work, we carried out rational design and syntheses of two series of OBHS analogs, namely OBHS-A (for acetamido derivatives), and OBHS-P (for propargyl derivatives), while we explored a synthetic methodology for a third series of OBHS compounds. Many analogs from the OBHS-A series exhibited high binding affinity. For example, the exo diastereomer of 2.11a, 2.11b, 2.11c, 2.11d, and 2.11e exhibited Relative Binding Affinities (RBAs) of 22.6%, 10.5%, 19.5%, 12.1%, and 14.4%, respectively. As observed before, endo OBHS compounds exhibited lower binding affinities than exo compounds. The RBA values with acetamide, and isobutyramide (i.e. short hydrophobic chains) were very comparable to each other. However, unexpectedly the propionamide compound showed lower binding affinity than butyramide. Nevertheless, we consider OBHS analogs with RBA values greater than 1% (Kd = 20 nM) to be very potent. This data is only the first step in a battery of assays that will be conducted eventually on these compounds. In particular, our emphasis is in ascertaining and improving the NF-kappa B mediated anti-inflammatory property, where these compounds have shown promising activity in conjunction with their anti-proliferative activity. / Master of Science

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 91-106).

Uterine leiomyomas are benign tumors within the uterus, where patients present with symptoms such as abnormal bleeding, urinary retention, and pelvic pressure. The exact etiology of uterine leiomyomas is unknown, but numerous theories have been proposed, indicating a multifactorial mechanism, including lifestyle and steroid hormones. Uterine leiomyomas have become a public health concern due to the high cost of treatment as well as the high prevalence within African American communities. Currently, many treatment options exist, ranging from conservative treatments that address symptoms, to surgical intervention to remove the uterus. Research efforts thus far have determined the relationship between the role of estrogen in the growth of uterine leiomyomas (which has led to development of medications that target different approaches to estrogen synthesis) and its effects in the pathogenesis. Studies have shown that estrogen acts on estrogen receptor subtypes, ER and ER. This study examines the role of these two receptors in estrogenic effects, and how these effects relate to the development of uterine leiomyomas. Available research has shown that each receptor has its unique functions and impacts the growth of tumors differently. There is conflicting evidence in how the number of receptors and surrounding environment modulate leiomyomas, with some studies reporting that it is the corepressors and/or coactivators that ultimately determine the influence of estrogenic effects. However, the general consensus of such studies suggests that estrogen receptor-specific therapeutic intervention is a novel area with great potential. The primary benefit of estrogen receptor-specific treatment, such as selective estrogen receptor modulators, is the ability to regulate physiological processes that contribute to the growth of uterine leiomyomas. Future directions of research include confirming the exact roles of ER and ER and harnessing the effects of their differing functions to manage uterine leiomyomas.

Leung Hok Sum. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (leaves 128-147). / Abstracts in English and Chinese. / Declaration --- p.i / Acknowledgements --- p.ii / Abbreviation --- p.iii / Abstract in English --- p.iv / Abstract in Chinese --- p.vi / Contents --- p.viii / Chapter Chapter I - --- Introduction / Chapter 1.1. --- Steroid Hormone --- p.1 / Chapter 1.2. --- Estrogen Receptors --- p.2 / Chapter 1.3. --- Selective Estrogen Receptor Modulators --- p.5 / Chapter 1.3.1. --- Tamoxifen --- p.5 / Chapter 1.3.1.1. --- Cardiovascular Effects of Tamoxifen --- p.6 / Chapter 1.3.1.2. --- Acute Vascular Effects of Tamoxifen --- p.6 / Chapter 1.3.1.3. --- Chronic Vascular Effects of Tamoxifen --- p.7 / Chapter 1.3.1.4. --- Antioxidant Effects of Tamoxifen --- p.8 / Chapter 1.3.2. --- Raloxifene --- p.8 / Chapter 1.3.2.1. --- Cardiovascular Effects of Raloxifene --- p.8 / Chapter 1.3.2.2. --- Acute Vascular Effects of Raloxifene --- p.9 / Chapter 1.3.2.3. --- Chronic Vascular Effects of Raloxifene --- p.10 / Chapter 1.3.2.4. --- Ovariectomy and Raloxifene Treatment --- p.11 / Chapter 1.4. --- Mechanism of Action of SERMs --- p.15 / Chapter 1.5. --- Effects of Functional Endothelium and Nitric Oxide --- p.18 / Chapter 1.6. --- Dihydropyridine (DHP) Calcium Channel Antagonists --- p.19 / Chapter 1.6.1. --- Development of Newer Generation of Dihydropyridines --- p.19 / Chapter 1.6.2. --- Effects of Dihydropyridines on Vascular Endothelium (I) --- p.20 / Chapter 1.6.3. --- Effects of Dihydropyridines on Vascular Endothelium (II) --- p.21 / Chapter 1.6.4. --- Effects of Dihydropyridines on Nitric Oxide Synthase (NOS) --- p.21 / Chapter 1.6.5. --- Clinical Studies of Dihydropyridines --- p.22 / Chapter 1.7. --- Vascular Ion Channels --- p.25 / Chapter 1.8. --- Objectives of The Present Study --- p.26 / Chapter Chapter II - --- Materials and Methods / Chapter 2.1. --- Tissue Preparation --- p.27 / Chapter 2.1.1. --- Preparation of The Porcine Left Circumflex Coronary Arteries --- p.27 / Chapter 2.1.2. --- Removal of Functional Endothelium --- p.27 / Chapter 2.1.3. --- Organ Bath Setup --- p.27 / Chapter 2.1.4. --- Isometric Force Measurement --- p.29 / Chapter 2.2. --- In situ Endothelial [Ca2+]i Imaging --- p.29 / Chapter 2.2.1. --- Preparation of Porcine Left Circumflex Coronary Arteries --- p.29 / Chapter 2.2.2. --- Setup For In situ Endothelial [Ca2+]i Imaging --- p.30 / Chapter 2.3. --- Electrophysiological Measurement of BKCa Current --- p.31 / Chapter 2.3.1. --- Enzymatic Dissociation of Coronary Artery Smooth Muscle Cells --- p.31 / Chapter 2.3.2. --- Electrophysiological Measurement --- p.31 / Chapter 2.4. --- DPPH Free Radical Scavenging Assay --- p.31 / Chapter 2.5. --- Solutions and Drugs --- p.32 / Chapter 2.5.1. --- "Drugs, Chemicals and Enzymes" --- p.32 / Chapter 2.5.2. --- Solutions Used in Force Measurement --- p.34 / Chapter 2.6. --- Statistical Analysis --- p.34 / Chapter Chapter III - --- Tamoxifen-Induced Endothelial Nitric Oxide-Dependent Relaxation in Porcine Coronary Arteries via Ouabain- and BaCl2-Sensitive Mechanisms / Chapter 3.1. --- Abstract --- p.35 / Chapter 3.2. --- Introduction --- p.36 / Chapter 3.3. --- Methods and Materials --- p.37 / Chapter 3.3.1. --- Vessel Preparation --- p.37 / Chapter 3.3.2. --- Isometric Force Measurement --- p.38 / Chapter 3.3.3. --- In situ Endothelial [Ca2+]i Imaging --- p.39 / Chapter 3.3.4. --- Chemicals --- p.40 / Chapter 3.3.5. --- Data Analysis --- p.40 / Chapter 3.4. --- Results --- p.41 / Chapter 3.4.1. --- Relaxant Responses --- p.41 / Chapter 3.4.2. --- Effects of Inhibitors of NO-Dependent Relaxation --- p.41 / Chapter 3.4.3. --- Effects of Putative K+ Channel Blockers and Ouabain --- p.41 / Chapter 3.4.4. --- "Effects of Ouabain, Removal of Extracellular K+ Ions and BaCI2" --- p.42 / Chapter 3.4.5. --- SNP-Induced Relaxation --- p.42 / Chapter 3.4.6. --- Effects of Actinomycin D and Cycloheximide --- p.42 / Chapter 3.4.7. --- Relaxant Effect of 17β-Estradiol --- p.43 / Chapter 3.4.8. --- Effects on Endothelial [Ca2+]i in Isolated Coronary Arteries With Endothelium --- p.43 / Chapter 3.5. --- Discussion --- p.53 / Chapter Chapter IV - --- Endothelium-Independent Relaxation to Raloxifene in Porcine Coronary Arteries / Chapter 4.1. --- Abstract --- p.57 / Chapter 4.2. --- Introduction --- p.58 / Chapter 4.3. --- Methods and Materials --- p.59 / Chapter 4.3.1. --- Vessel Preparation --- p.59 / Chapter 4.3.2. --- Isometric Force Measurement --- p.60 / Chapter 4.3.3. --- Electrophysiological Measurement of BKCa Current --- p.61 / Chapter 4.3.3.1. --- Enzymatic Dissociation of Coronary Artery Smooth Muscle --- p.61 / Chapter 4.3.3.2. --- Electrophysiological Measurement --- p.62 / Chapter 4.3.4. --- Chemicals --- p.63 / Chapter 4.3.5. --- Data Analysis --- p.63 / Chapter 4.4. --- Results --- p.64 / Chapter 4.4.1. --- Effect of Raloxifene on Agonist-Induced Contractions --- p.64 / Chapter 4.4.2. --- Role of Endothelium --- p.64 / Chapter 4.4.3. --- Effect of ER Antagonist --- p.65 / Chapter 4.4.4. --- Effect of Putative K+ Channel Blockers --- p.65 / Chapter 4.4.5. --- Effect of Elevated Extracellular K+ Concentrations --- p.65 / Chapter 4.4.6. --- Effects of Raloxifene on BKCa Current --- p.65 / Chapter 4.5. --- Discussion --- p.75 / Chapter Chapter V - --- Therapeutic Concentrations of Raloxifene Augment Bradykinin Mediated Nitric Oxide-Dependent Relaxation in Porcine Coronary Arteries / Chapter 5.1. --- Abstract --- p.78 / Chapter 5.2. --- Introduction --- p.79 / Chapter 5.3. --- Methods and Materials --- p.80 / Chapter 5.3.1. --- Vessel Preparation --- p.80 / Chapter 5.3.2. --- Isometric Force Measurement --- p.80 / Chapter 5.3.3. --- In situ Endothelial [Ca2+]i Imaging --- p.81 / Chapter 5.3.4. --- Free Radical Scavenging Assay --- p.82 / Chapter 5.3.5. --- Chemicals --- p.83 / Chapter 5.3.6. --- Data Analysis --- p.83 / Chapter 5.4. --- Results --- p.84 / Chapter 5.4.1. --- Relaxation to Bradykinin --- p.84 / Chapter 5.4.2. --- Effect of Raloxifene on Bradykinin-Induced Relaxation --- p.84 / Chapter 5.4.3. --- Effect of Raloxifene on Relaxation Induced by Substance P and --- p.85 / Chapter 5.4.4. --- Effect of Estrogen on Bradykinin-Induced Relaxation --- p.85 / Chapter 5.4.5. --- Effect of Raloxifene on Sodium Nitroprusside-Induced Relaxation --- p.86 / Chapter 5.4.6. --- Free Radical Scavenging Effect --- p.86 / Chapter 5.4.7. --- Raloxifene Augmentation of Bradykinin-Stimulated Endothelial [Ca2+]i --- p.86 / Chapter 5.5. --- Discussion --- p.99 / Chapter Chapter VI - --- "Cilnidipine, a Slow-Acting Ca2+ Channel Blocker, Induces Relaxation in Porcine Coronary Arteries: Role of Endothelial Nitric Oxide and [Ca2+]i" / Chapter 6.1. --- Abstract --- p.102 / Chapter 6.2. --- Introduction --- p.103 / Chapter 6.3. --- Methods and Materials --- p.104 / Chapter 6.3.1. --- Vessel Preparation --- p.104 / Chapter 6.3.2. --- Isometric Force Measurement --- p.105 / Chapter 6.3.3. --- In situ Endothelial [Ca2+]i Imaging --- p.106 / Chapter 6.3.4. --- Free Radical Scavenging Assay --- p.107 / Chapter 6.3.5. --- Chemicals --- p.108 / Chapter 6.3.6 --- Data Analysis --- p.108 / Chapter 6.4. --- Results --- p.108 / Chapter 6.4.1. --- Relaxant Responses --- p.108 / Chapter 6.4.2. --- Role of the Endothelium --- p.109 / Chapter 6.4.3. --- Effect of Inhibitors of NO-Dependent Relaxation --- p.109 / Chapter 6.4.4. --- Effect of Indomethacin and w-conotoxin --- p.110 / Chapter 6.4.5. --- Effect of Cilnidipine on Sodium Nitroprusside-Induced Relaxation --- p.110 / Chapter 6.4.6. --- Effects on Endothelial [Ca2+]i in Isolated Endothelium-Intact Coronary Arteries --- p.110 / Chapter 6.4.7. --- Free Radical Scavenging Effect --- p.110 / Chapter 6.5. --- Discussion --- p.120 / Chapter Chapter VII - --- General Summary --- p.123 / References --- p.128

Obesity is a grave disease that is increasing in global prevalence. Aberrant neuronal DNA methylation patterns have been implicated in the promotion of obesity development, but the role of neuronal DNA methyltransferases (Dnmts; enzymes that catalyze DNA methylation) in energy balance remains poorly understood. We investigated the role of neuronal Dnmt1 in normal energy regulation and obesity development using a novel Dnmt1 knockout mouse model, Dnmt1fl/fl Synapsin1Cre (ND1KO), which specifically deletes Dnmt1 in neurons. ND1KO and fl/fl control littermates were fedeither a standard chow diet or a high fat diet (HFD). We conducted a deep analysis to characterize both peripheral and central aspects of the ND1KO phenotype. We found that neuronal Dnmt1 deficiency reduced adiposity in chow-fed mice and attenuated obesity in HFD-fed male mice. ND1KO male mice had reduced food intake and increased energy expenditure on the HFD. Furthermore, these mice had improved insulin sensitivity as measured by an insulin tolerance test. HFD-fed ND1KO mice had smaller fat pads and an upregulation of thermogenic genes in brown adipose tissue. These data suggest that neuronal Dnmt1 deletion increased diet-induced thermogenesis, which may explain the lean phenotype in HFD-fed ND1KO mice. Interestingly, we found that ND1KO male mice had elevated estrogen receptor-α gene expression in the hypothalamus, which previously has been shown to control body weight. Immunohistochemistry experiments revealed that estrogen receptor-α (ERα) protein expression was upregulated in the dorsomedial region of the VMH (VMHdm), a region which may mediate the central effect of leptin. Finally, we tested whether ND1KO mice had reduced methylation of the ERα gene promoter, which might explain the ERα upregulation. Neuronal Dnmt1 deficiency decreased methylation at two CpG sites on Exon A in chow-fed mice. Collectively, these data suggest that neuronal Dnmt1 regulates energy homeostasis through pathways controlling food intake and energy expenditure, and that ERα in the VMHdm may mediate these effects.

Breast cancer is the second leading cause of cancer-related death in women. Mutations in the tumor suppressor gene BRCA-1 confer a high risk of breast tumor development. However, in sporadic breast cancers, which represent 90-95% of breast cancer cases, BRCA-1 expression is downregulated in the absence of mutations in the BRCA-1 gene. This suggests that epigenetic effectors may contribute to disruption of BRCA-1 expression and the onset of mammary tumors.Prototypical environmental contaminants found in industrial pollution, tobacco smoke, and cooked foods include benzo[a]pyrene (B[a]P) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which have been shown to alter mammary gland development, act as endocrine disruptors and tumor promoters. Population studies detected accumulation of TCDD in women's adipose tissue and breast milk. Moreover, sporadic breast tissue exhibited statistically significant higher levels of PAH-DNA adducts. Based on this information, we examined the effect of B[a]P on the tumor suppressor BRCA-1and observed that exposure to B[a]P led to repression of BRCA-1 transcription through a p53-dependent mechanism. We have also demonstrated that 17β-estradiol (E2) stimulated the recruitment of ERα and AP-1 family members to a region of the BRCA-1 promoter flanking an AP-1-like site. However, accumulation of p53 prevented E2-mediated BRCA-1 transcription and recruitment of ERα, potentially providing one mechanism of B[a]P-mediated repression.In addition, the effects of B[a]P and TCDD are mediated through binding of the liganded aromatic hydrocarbon receptor (AhR) to dioxin or xenobiotic-responsive elements (XRE). We have evidence that suggests B[a]P and TCDD may modulate repression of E2-stimulated BRCA-1 expression through 1) binding of the liganded AhR to XREs on the BRCA-1 promoter and 2) preventing promoter occupancy by p300 and SRC-1.Taken together, the data presented here suggest that the transcriptional regulation of BRCA-1 is complex and involves modulation of the recruitment of ERα, AhR, p53, and their cofactors. An important implication of these findings is a greater understanding of the role of ERα, AhR, and p53 in regulation of BRCA-1 which could lead to the development of therapeutic strategies that target these interactions to enhance upregulation of BRCA-1 expression in sporadic breast tumors.

The incidence of cardiovascular diseases including cardiac hypertrophy and failure in pre-menopausal women is lower compared to age-matched men but the risk of heart disease increases substantially after the onset of menopause. It has been postulated that female sex hormones play an important role in cardiovascular health in pre-menopausal women. In animal studies including spontaneously hypertensive (SHR) rats, the development of cardiac hypertrophy is attenuated by 17&#946;-estradiol treatment. Cardiac energy metabolism is crucial for normal function of the heart. In cardiac hypertrophy and heart failure, the myocardium undergoes a metabolic shift from fatty acid as primary cardiac energy source to glucose, which re-introduces the fetal type of metabolism that representing the glucose as a major source of energy. Many studies have reported that the disruption of the balance between glucose and fatty acid metabolism plays an important role in cardiac pathologies including hypertrophy, heart failure, diabetes, dilative cardiomyopathy and myocardial infarction. Glucose enters cardiomyocytes via GLUT1 and GLUT4 glucose transporters and GLUT4 is the major glucose transporter which is insulin-dependent. Cardiac-selective GLUT4 deficiency leads to cardiac hypertrophy. This shows that the decrease in cardiac glucose uptake may play a direct role in the pathogenesis of cardiac hypertrophy. Estrogens modulate glucose homeostasis in the liver and the skeletal muscle. But it is not known whether estrogens affect also cardiac glucose uptake which could provide another mechanism to explain the prevention of cardiac hypertrophy by female sex hormones. In the present study, SHR Rats were ovariectomized (OVX), not ovariectomized (sham) or ovariectomized and treated with subcutaneous 17&#946;-estradiol. After 6 weeks of treatment, body weight, the serum levels of estrogen, insulin, intra-peritoneal glucose tolerance test (IP-GTT), myocardial glucose uptake by FDG-PET (2-(18F)-fluoro-deoxyglucose (18FDG) and Positron Emission Tomography), cardiac glucose transporter expression and localization and cardiac hexokinase activity were analyzed. As results of this study, PET analysis of female SHR revealed decreased cardiac glucose uptake in OVX animals compared to intact that was normalized by estrogen supplementation. Interestingly, there was no change in global glucose tolerance among the treatment groups. Serum insulin levels and cardiac hexokinase activity were elevated by E2 substitution. The protein content of cardiac glucose transporters GLUT-4 and GLUT-1, and their translocation as determined by fractionation studies and immuno-staining did not show any significant change by ovariectomy and estrogen replacement. Also levels of insulin receptor substrate-1 (IRS-1) and its tyrosine phosphorylation, which is required for activation and translocation of GLUT4, was un-affected in all groups of SHR. Cardiac gene expression analysis in SHR heart showed that ei4Ebp1 and Frap1 genes which are involved in the mTOR signaling pathway, were differentially expressed upon estrogen treatment. These genes are known to be activated in presence of glucose in the heart. As a conclusion of this study, reduced myocardial FDG uptake in ovariectomized spontaneously hypertensive rat is normalized by 17&#946;-estradiol treatment. Increased myocardial hexokinase appears as a potential mechanism to explain increased myocardial glucose uptake by 17&#946;-estradiol. Increased cardiac glucose uptake in response to 17&#946;-estradiol in ovariectomized SHR may provide a novel mechanism to explain the reduction of cardiac hypertrophy in E2 treated SHR. Therefore, 17&#946;-estradiol improves cardiac glucose utilization in ovariectomized SHR which may give rise to possible mechanism for its protective effects against cardiac hypertrophy. / Erkrankungen des kardiovaskulären Systems, wie beispielsweise Herzhypertrophie oder Herzinsuffizienz treten bei Frauen vor der Menopause im Vergleich zu gleichaltrigen Männern seltener auf. Das Risiko für eine solche kardiovaskuläre Erkrankung steigt jedoch drastisch mit dem Beginn der Menopause an. Aus diesem Grund wird angenommen, dass weibliche Geschlechtshormone kardioprotektive Wirkungen besitzen. Tierstudien an spontan hypertensiven Ratten (SHR) haben belegt, dass eine Herzhypertrophie durch die Behandlung der Tiere mit 17&#946;-Estradiol abgemildert werden kann. Entscheidend für die Funktion des Myokards ist sein Energiemetabolimus, der sich im Verlauf einer Hypertrophie oder Herzinsuffizienz vom primären Fettsäurestoffwechsel auf Glucosemetabolismus umschaltet. Diese Situation entspricht der des fetalen Herzens. Viele Studien haben belegt, dass eine Störung der Balance zwischen Glucose- und Fettsäurestoffwechsel oftmals ein erstes Anzeichen für einen pathologischen Zustand des Herzens, wie z.B. Hypertrophie, Herzinsuffizienz, Diabetes, dilative Kardiomyopathie und Myokardinfarkt ist. Im gesunden Herzen gelangt Glucose über die zwei Glucosetransporter GLUT1 und GLUT4 in die Zellen des Myokards, wobei der insulinabhängige Glut4-Transporter der Hauptglucosetransporter ist. Eine GLUT4-Defizienz führt daher ebenfalls zu einer Herzhypertrophie was wiederum zeigt, dass eine verminderte Glucoseaufnahme im direkten Zusammenhang mit pathologischen Zuständen des Herzens steht. Bisherige Studien haben gezeigt, dass Östrogen an der Glucosehomöostase in Leber und Skelettmuskeln beteiligt ist. Jedoch ist wenig darüber bekannt, ob Östrogen ebenfalls in die kardiale Glucosehomöostase eingreift und inwiefern die kardioprotektive Wirkung des Östrogens in diesem Zusammenhang steht.In der vorliegenden Arbeit wurden weibliche SH-Ratten ovariektomiert (OVX), nicht ovariektomiert (sham) oder ovariektomiert und zusätzlich subkutan mit 17&#946;-Estradiol behandelt. Nach einer Behandlungszeit von 6 Wochen wurden dann das Körpergewicht, die Serumspiegel von Östrogen, Insulin und IPGTT bestimmt, und die Glucoseaufnahme des Myokards mittels FDG-PET analysiert. Zusätzlich wurden Expression und zelluläre Lokalisation der kardialen Glucosetransporter sowie die kardiale Hexokinaseaktivität untersucht. Es konnte gezeigt werden, dass sich eine verminderte Glucoseaufnahme des Herzens bei ovariektomierten Tieren durch Östrogen-Supplementation normalisieren lässt. Eine Abweichung bezüglich der Glucosetoleranz der einzelnen Gruppen konnte nicht beobachtet werden. Jedoch konnte ein erhöhter Insulinspiegel des Serums und eine erhöhte kardiale Aktivität des Enzyms Hexokinase durch die Behandlung mit Östrogen bei den ovariektomierten Tieren beschrieben werden. Durch Fraktionierungen und immunhistologische Untersuchungen konnte kein signifikanter Unterschied in Bezug auf die Menge sowie die Translokation der Glucosetransporter GLUT1 und GLUT4 im Myokard zwischen den einzelnen Behandlungen der Tiere beschrieben werden. Ferner konnte zwischen den einzelnen Tiergruppen auch kein Unterschied zwischen dem Insulin Rezeptor Substrat-1 (IRS-1) und seiner Tyrosin-phosphorylierten Form festgestellt werden, die für die Aktivierung und Translokation des GLUT4 benötigt werden. Analysen der Genexpression in den Herzen der SH-Ratten konnten allerdings zeigen, dass die Gene ei4Ebp1 und Frap1, die im mTOR Signalweg involviert sind, bei den Östrogen-supplementierten Tieren ein abweichendes Expressionsmuster aufweisen. Über diese Gene ist bekannt, dass sie in der Gegenwart von Glucose im Herzen aktiviert werden und bei der Entstehung einer Herzhypertrophie mitwirken. Basierend auf den PET-Analysen und der Hexokinaseaktivität lässt sich als Resultat dieser Arbeit aussagen, dass Östrogen die kardiale Glucoseaufnahme in SH-Ratten fördert. Diese Ergebnisse könnten einen Hinweis auf einen noch unbekannten Mechanismus geben, um die protektive Wirkung des Östrogens im Hinblick auf die Herzhypertrophie zu erklären. Hinsichtlich der Tatsache, dass keine Veränderungen in der Translokation der GLUT4-Transporter in der Plasmamembran bei den einzelnen Behandlungen der Tiere zu verzeichnen sind, jedoch Veränderungen der Glucoseaufnahme durch die PET-Analysen dargestellt werden konnten, besteht jedoch noch Erklärungsbedarf. Es liegen diverse Studien vor, die diesen Unterschied damit erklären könnten, dass der GLUT4-Transporter in einer inaktiven Form in der Plasmamembran vorliegt bis die Glucoseaufnahme durch den GLUT4-Transporter mittels der Insulin Signaltransduktionskaskade reguliert wird.