Role of 17β-hydroxysteroid dehydrogenase in the hypertension of PCOS

17β-羟基类固醇脱氢酶在 PCOS 高血压中的作用

• 批准号: 9211439
• 负责人: LICY LORENA YANES CARDOZO
• 金额: $ 30.96万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-08 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9211439
• 关键词: Adipose tissue; Affect; Age; Androgen Receptor; Androgens; Angiotensin-Converting Enzyme Inhibitors; Animal Model; Animals; Attention; Blood Pressure; Body Weight decreased; Cardiovascular Abnormalities; Clinical; Data; Development; Eating; Enalapril; Endocrine System Diseases; Ethnic Origin; Etiology; Exposure to; Female; Hirsutism; Hydroxysteroid Dehydrogenases; Hyperandrogenism; Hypertension; Infertility; Insulin Resistance; Lead; Life Style; Mediating; Menstruation; Metabolic; Mississippi; Modeling; Morphology; Natriuresis; Obesity; Ovarian; Patients; Perinatal; Physiological; Plasma; Play; Polycystic Ovary Syndrome; Prevalence; Production; Rattus; Renin-Angiotensin System; Research; Role; Stanolone; Syndrome; Testing; Therapeutic; Woman; base; blood pressure regulation; cardiovascular risk factor; clinically relevant; fertility improvement; imaging modality; implantation; improved; molecular imaging; novel; prenatal; pressure; reproductive; subcutaneous; theories; tool

PROJECT III: ROLE OF 17Β-HYDROXYSTEROID DEHYDROGENASE IN THE HYPERTENSION OF PCOS. SUMMARY Polycystic Ovary Syndrome (PCOS) is characterized by increases in plasma androgens and/or hirsutism, irregular menstrual periods, ovarian cystic morphology and infertility. Although the etiology of PCOS is unknown, one theory is that PCOS may be developmentally programmed due to exposure to prenatal androgens. PCOS is one of the most common female endocrine disorders, affecting 5 to 26% of women of reproductive age depending on ethnicity and lifestyle. Recent attention in women with PCOS in the US has focused on several metabolic derangements such as obesity, insulin resistance and hypertension. In the US the prevalence of obesity in PCOS women is up to 80%. Obesity plays a major role in the clinical manifestations of the syndrome, since weight loss is associated with improved fertility and reductions in metabolic derangements in PCOS patients. Several lines of evidence indicate that there is a positive relationship between circulating levels of androgens, obesity, insulin resistance and blood pressure (BP) in women with PCOS. Whether and how increases in circulating androgens cause obesity, insulin resistance and hypertension in PCOS women remains poorly understood and is the main focus of this proposal. We have established an animal model of PCOS in female rats that mimics many of the metabolic and cardiovascular abnormalities of women with PCOS. Implantation of dihydrotestosterone (DHT) pellets in female rats causes an increase in food intake, subcutaneous adipose tissue, insulin resistance, obesity, and elevated BP, as observed in PCOS women. In this proposal we will test the hypothesis that in PCOS, increased plasma androgens via the androgen receptor cause an increase in food intake leading to obesity that includes an increase in subcutaneous adipose tissue, and insulin resistance. The combination of increased circulating androgens, obesity and insulin resistance activate adipose 17β-HSD, resulting in increased adipose androgen synthesis that further increases circulating androgen levels setting up a vicious cycle. Increased circulating androgens lead to subsequent activation of the intrarenal renin angiotensin system and elevated blood pressure. This hypothesis will be tested using an integrative physiological approach using whole animal, cellular, molecular and imaging methods in the following specific aims: 1) to test the hypothesis that increased circulating androgens via activation of the androgen receptor promotes obesity with an increase in subcutaneous adipose tissue and insulin resistance in PCOS; 2) to test the hypothesis that increases in subcutaneous adipose tissue and insulin resistance lead to activation of 17β-HSD in the subcutaneous adipose tissue, thus further increasing circulating levels of androgens in PCOS; 3) to test the hypothesis that increased circulating androgens activate the intrarenal renin-angiotensin system (RAS), shifting the pressure-natriuresis curve to the right, leading to increases in blood pressure in PCOS; 4) to test the hypothesis that either elevated circulating androgens or activation of the RAS by androgens leads to insulin resistance in PCOS independently of obesity. This novel and clinically relevant proposal will elucidate potential mechanisms by which androgens regulate blood pressure, promote obesity and insulin resistance in women with PCOS, determine the pathophysiological interactions between these cardiovascular risk factors and will pave the way to identify novel and improved therapeutic tools to treat the clinical manifestations associated with hyperandrogenism in PCOS women.

项目III：17 β-羟基甾醇脱氢酶在PCOS高血压中的作用。 总结 多囊卵巢综合征（PCOS）的特征是血浆雄激素增加和/或多毛症， 月经不调、卵巢囊性形态和不孕症。虽然PCOS的病因是 未知，一种理论是，PCOS可能是由于暴露于产前 雄激素PCOS是最常见的女性内分泌疾病之一，影响5%至26%的女性， 生育年龄取决于种族和生活方式。最近在美国多囊卵巢综合征妇女的关注， 集中于几种代谢紊乱，如肥胖、胰岛素抵抗和高血压。在美国 PCOS妇女肥胖患病率高达80%。肥胖症在临床上起着重要的作用， 综合征的表现，因为体重减轻与提高生育能力和减少 PCOS患者的代谢紊乱。几条证据表明，有一个积极的 雄激素循环水平、肥胖、胰岛素抵抗和血压之间的关系 PCOS的女性循环雄激素的增加是否以及如何导致肥胖、胰岛素抵抗和 PCOS妇女的高血压仍然知之甚少，这是这项建议的主要焦点。 我们已经在雌性大鼠中建立了PCOS动物模型，该模型模拟了许多代谢和 PCOS妇女的心血管异常。双氢睾酮（DHT）微丸植入 雌性大鼠引起食物摄入、皮下脂肪组织、胰岛素抵抗、肥胖和 血压升高，如PCOS妇女所观察到的。 在本研究中，我们将检验PCOS患者血浆雄激素水平升高是通过雄激素受体介导的这一假说。 受体引起食物摄入增加，导致肥胖，包括皮下脂肪增加， 组织和胰岛素抵抗。循环雄激素增加、肥胖和胰岛素 抵抗激活脂肪17 β-HSD，导致脂肪雄激素合成增加， 循环中的雄激素水平形成恶性循环循环雄激素增加导致随后的 肾内肾素血管紧张素系统的激活和血压升高。这一假设将是 使用完整动物、细胞、分子和成像的综合生理方法进行测试 方法的具体目的如下：1）检验通过以下途径增加循环雄激素的假设： 雄激素受体的激活促进肥胖，皮下脂肪组织增加， PCOS中的胰岛素抵抗; 2）检验皮下脂肪组织和胰岛素增加的假设， 抵抗导致皮下脂肪组织中17 β-HSD的活化，从而进一步增加循环 雄激素水平的PCOS; 3）测试的假设，增加循环雄激素激活的PCOS， 肾内肾素-血管紧张素系统（RAS），使压力-尿钠排泄曲线向右移动，导致 PCOS患者血压升高; 4）检验循环雄激素升高或 雄激素对RAS的激活导致PCOS的胰岛素抵抗，与肥胖无关。 这个新的和临床相关的建议将阐明潜在的机制，雄激素调节 血压，促进肥胖和胰岛素抵抗的PCOS妇女，确定病理生理 这些心血管危险因素之间的相互作用，并将铺平道路，以确定新的和改进的 治疗工具，以治疗PCOS妇女高雄激素血症相关的临床表现。