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: 10189643
• 负责人: LICY LORENA YANES CARDOZO
• 金额: $ 43.83万
• 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 2022-08-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189643
• 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：17β-羟基类固醇脱氢酶在 PCOS 高血压中的作用。 概括 多囊卵巢综合症（PCOS）的特点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。虽然 PCOS 的病因是 未知，一种理论认为，多囊卵巢综合症可能是由于产前接触过 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，美国多囊卵巢综合征女性受到关注 重点关注多种代谢紊乱，如肥胖、胰岛素抵抗和高血压。在美国 PCOS女性肥胖患病率高达80%。肥胖在临床上起着重要作用 该综合征的表现，因为体重减轻与生育能力的提高和生育力的减少有关 PCOS 患者的代谢紊乱。多项证据表明，存在积极的影响 雄激素循环水平、肥胖、胰岛素抵抗和血压（BP）之间的关系 患有多囊卵巢综合症的女性。循环雄激素的增加是否以及如何导致肥胖、胰岛素抵抗和 多囊卵巢综合症女性的高血压仍然知之甚少，这是该提案的主要焦点。 我们在雌性大鼠中建立了多囊卵巢综合症动物模型，该模型模拟了许多代谢和 患有 PCOS 的女性心血管异常。将二氢睾酮 (DHT) 颗粒植入体内 雌性大鼠会导致食物摄入量、皮下脂肪组织增加、胰岛素抵抗、肥胖和 血压升高，如在多囊卵巢综合症女性中观察到的那样。 在本提案中，我们将测试以下假设：在 PCOS 中，通过雄激素增加血浆雄激素 受体导致食物摄入量增加，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、肥胖和胰岛素的结合 抵抗激活脂肪 17β-HSD，导致脂肪雄激素合成增加，从而进一步增加 循环雄激素水平形成恶性循环。循环雄激素增加导致随后 激活肾内肾素血管紧张素系统并升高血压。这个假设将是 使用整体动物、细胞、分子和成像的综合生理学方法进行测试 方法具有以下具体目的：1）检验通过以下方式增加循环雄激素的假设： 雄激素受体的激活会导致皮下脂肪组织增加，从而促进肥胖 多囊卵巢综合征的胰岛素抵抗； 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17β-HSD的激活，从而进一步增加循环 多囊卵巢综合症患者的雄激素水平； 3）检验循环雄激素增加激活 肾内肾素-血管紧张素系统（RAS），将压力-尿钠曲线向右移动，导致 多囊卵巢综合症患者血压升高； 4）检验循环雄激素升高或 雄激素激活 RAS 会导致 PCOS 患者胰岛素抵抗，与肥胖无关。 这项新颖且具有临床意义的提案将阐明雄激素调节的潜在机制 血压，促进 PCOS 女性肥胖和胰岛素抵抗，确定病理生理学 这些心血管危险因素之间的相互作用将为识别新的和改进的方法铺平道路 治疗多囊卵巢综合征女性与高雄激素血症相关的临床表现的治疗工具。