Gestational Hyperandrogenism in Cardiovascular Programming

心血管规划中的妊娠期雄激素过多症

• 批准号: 10256011
• 负责人: VASANTHA PADMANABHAN
• 金额: $ 70.33万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256011
• 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; Left ventricular structure; 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; Structure; 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%。 死亡在美国。令人信服的人类流行病学数据表明， 环境导致宫内生长受限，与CVD风险增加相关， 左心室肥大已发现产前暴露于过量的睾酮（T） 在经过充分验证的绵羊发育规划模型中对多器官系统进行编程。产前T 在该模型中，过量诱导两种性别的IUGR，并最终导致胰岛素抵抗，左心室功能增加， 女性后代成年后的体重和高血压（产前T对心脏代谢的影响） 尚未研究雄性后代的结果）。考虑到CVD中存在的两性异形 死亡率和发病率，这是至关重要的是要深入了解的作用，性二型性发挥在左 心室肥大，使性别特异性的预防策略的发展。在这方面，产前 T模型提供了一个有价值的资源，以确定在多大程度上过量性类固醇暴露通过疾病 状态（多囊卵巢综合征，先天性肾上腺皮质增生，或环境化学品， 在胎儿发育过程中类固醇生成的潜力， 成年期CVD死亡率增加。我们的初步数据提供了证据，产前T过量导致 成年雌性后代的病理性左心室重塑，从而使我们能够探索潜在的 机制和性别特异性功能结果。本申请的目的是确定 子宫内暴露于过量T程序不良心脏重塑和易感性的机制 在成人生活中的心脏病，并辨别性别差异，可能存在于这个节目。我们 假设产前T过量将导致不利左心室结构和功能改变， 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，导致在以后的生活中对损伤的易感性增加。拟议 研究将提供对以下机制的深入了解：1）宫内过量T导致不利的左心室 重塑，2）产前T过量的长期心脏功能和结构后果和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确定 针对LVH和心力衰竭治疗的策略和翻译相关性。