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）是全球主要死亡原因之一，占总死亡人数的32.2% 美国的死亡人数。令人信服的人类流行病学数据表明，子宫内不良反应 环境导致宫内生长受限，这与心血管疾病和心血管疾病风险增加有关 左心室肥厚。产前暴露于过量睾酮 (T) 已被发现对 在经过充分验证的绵羊发育编程模型中对多个器官系统进行编程。产前检查 在此模型中，过量会诱发两性的 IUGR，并最终导致胰岛素抵抗、左心室增加 成年女性后代的体重和高血压（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中存在的性别二态性 死亡率和发病率 深入了解性别二态性在左翼中所起的作用至关重要 心室肥厚，以便制定针对性别的预防策略。对此，产前 T 模型提供了宝贵的资源，可用于确定疾病导致的过量性类固醇暴露程度 状态（多囊卵巢综合症、先天性肾上腺增生症或环境化学物质） 胎儿发育过程中的类固醇生成潜力 不利的心脏组织重塑导致 成年期 CVD 死亡率增加。我们的初步数据提供证据表明产前 T 过量导致 成年女性后代的病理性左心室重塑，从而使我们能够探究潜在的 机制和性别特异性功能结果。该应用程序的目的是确定 子宫内暴露于过量 T 程序导致不良心脏重塑和易感性的机制 成人生活中的心脏病，并辨别该编程中可能存在的性别差异。我们 假设产前 T 过剩将导致不良的左心室结构和功能变化 寿命和这些变化将由参与维持生命的途径的表观遗传修饰驱动 左心室形态和功能的改变导致晚年对损伤的易感性增加。拟议的 研究将深入了解 1) 子宫内 T 过多导致左心室不良的机制 重塑，2) 产前 T 过剩的长期心脏功能和结构后果，以及 3) 性别 产前心脏编程的差异。通过这些研究获得的知识将有助于识别 针对 LVH 和心力衰竭治疗且具有转化相关性的策略。