Gestational Hyperandrogenism in Cardiovascular Programming

心血管规划中的妊娠期雄激素过多症

• 批准号: 10472623
• 负责人: VASANTHA PADMANABHAN
• 金额: $ 3.55万
• 依托单位: CALIFORNIA NORTHSTATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-04 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10472623
• 关键词: Accounting; Address; Adult; Androgen Antagonists; Animal Model; Birth; Birth Weight; Blood Pressure Monitors; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cessation of life; Congenital adrenal hyperplasia; Congestive Heart Failure; Data; Development; Disease; Echocardiography; Environment; Epigenetic Process; Exposure to; Female; Fetal Development; Fetal Growth Retardation; Fetus; Flutamide; Functional disorder; Genetic Transcription; Gonadal Steroid Hormones; Growth; Health; Heart Diseases; Heart failure; Human; Hyperandrogenism; Hyperinsulinism; Hyperplasia; Hypertension; Hypertrophy; Insulin Resistance; Insulin Signaling Pathway; Knowledge; Lead; Left; Left Ventricular Hypertrophy; Left Ventricular Mass; Left Ventricular Remodeling; Life; Link; Longevity; Mediating; Mediator of activation protein; Modeling; Modification; Molecular; Morbidity - disease rate; Morphology; Myocardial dysfunction; Outcome; Pathologic; Pathway interactions; Play; Polycystic Ovary Syndrome; Predisposition; Pregnancy; Prevention strategy; Program Development; Resources; Risk; Secondary to; Sex Differences; Steroids; Testing; Testosterone; Therapeutic; Time; Tissues; United States; Ventricular; androgenic; body system; cardiometabolism; cardiovascular disorder risk; environmental chemical; epidemiologic data; fetal; functional outcomes; heart function; human data; in utero; insight; insulin sensitizing drugs; male; mortality; novel; offspring; prenatal; prenatal exposure; prevent; programs; rosiglitazone; sex; sexual dimorphism; sexual role; sheep model

Cardiovascular disease (CVD) is one of the leading causes of death worldwide accounting for 32.2% of all deaths in the United States. Compelling epidemiological data in human has shown that adverse in utero environment leads to intrauterine growth restriction that has been associated with increased risk of CVD and left ventricular hypertrophy. Prenatal exposure to excess testosterone (T) has been found to adversely program multiple organ systems in the well-validated sheep model of developmental programming. Prenatal T excess induces IUGR in both sexes in this model and culminates in insulin resistance, increased left ventricular mass and hypertension in the female offspring in adulthood (the impact of prenatal T on cardiometabolic outcomes in the male offspring has not been studied). Considering the sexual dimorphism that exists in CVD mortality and morbidity it is critically important to gain an insight into the role sexual dimorphism plays in left ventricular hypertrophy to enable development of sex-specific prevention strategies. In this regard, the prenatal T model provides a valuable resource to determine to what extent excess sex steroid exposure via disease states (Polycystic ovary syndrome, Congenital adrenal hyperplasia, or environmental chemicals with steroidogenic potential during fetal development programs adverse cardiac tissue remodeling resulting in increased mortality from CVD in adulthood. Our preliminary data provide evidence that prenatal T excess leads to pathological left ventricular remodeling in adult female offspring thus allowing us to probe underlying mechanisms and sex-specific functional outcomes. The objective of this application is to identify the mechanism(s) by which in utero exposure to excess T programs adverse cardiac remodeling and susceptibility to cardiac disease during adult life and to discern sex differences that might exist in this programming. We hypothesize that prenatal T excess will lead to adverse left ventricular structural and functional changes over the lifespan and these changes will be driven by epigenetic modifications of pathways involved in maintaining left ventricular morphology and function leading to increased susceptibility to insult later in life. The proposed studies will provide insight into the 1) mechanisms by which excess T in-utero leads to adverse left ventricular remodeling, 2) long term cardiac functional and structural consequences of prenatal T excess and 3) sex differences in prenatal cardiac programming. Knowledge gained through these studies will help identify strategies targeted toward treatment for LVH and heart failure and of translational relevance.

心血管疾病（CVD）是全球死亡的主要原因之一，占所有死亡的32.2％ 在美国死亡。人类中引人入胜的流行病学数据表明，子宫内的不利 环境导致宫内生长限制与CVD风险增加有关 左心室肥大。发现产前暴露于多余的睾丸激素（T）有不利 在经过充分验证的发育节目绵羊模型中编程多器官系统。产前t 在该模型中，多余的性别诱导IUGR，并在胰岛素抵抗中达到顶点，左心室增加 成年后女性后代的质量和高血压（产前T对心脏代谢的影响 尚未研究男性后代的结果）。考虑CVD中存在的性二态性 死亡率和发病率至关重要 心室肥大，以发展性别特异性预防策略。在这方面，产前 T模型提供了宝贵的资源，以确定多种程度的过量性类固醇通过疾病暴露 国家（多囊卵巢综合征，先天性肾上腺增生或环境化学物质 胎儿发育计划中的类固醇生成潜力不良心脏组织重塑，导致 成年后CVD的死亡率增加。我们的初步数据提供了证据表明产前T多余的潜在客户 在成年雌性后代进行病理左心室重塑，从而使我们能够探测底层 机制和性别特异性功能结果。此应用的目的是确定 在子宫内暴露于多余T程序的机制不良心脏重塑和易感性 在成人生活中为心脏病和辨别该节目中可能存在的性别差异。我们 假设产前T多余将导致左心室结构和功能变化不利 寿命和这些变化将由涉及的途径的表观遗传修饰驱动 左心室形态和功能，导致人们对以后的侮辱敏感性增加。提议 研究将提供有关1）多个t内导致左心室不良的机制的见解 重塑，2）产前T多余的长期心脏功能和结构后果和3）性 产前心脏编程的差异。通过这些研究获得的知识将有助于确定 旨在治疗LVH和心力衰竭以及转化相关性的策略。