Compositional and Functional Alterations of HDL Over Ovarian Aging

卵巢衰老过程中 HDL 的组成和功能变化

• 批准号: 10372025
• 负责人: Samar R El Khoudary
• 金额: $ 38.9万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372025
• 关键词: Acceleration; Address; Adopted; Aging; Ancillary Study; Antiatherogenic; Antiinflammatory Effect; Apoptotic; Atherosclerosis; Biological; Biological Markers; Blood specimen; Body Composition; C-reactive protein; Cardiovascular Diseases; Cause of Death; Cells; Cholesterol; Chronic; Clinical; Clinical Trials Design; Complement; Complex; Data; Data Set; Data Store; Development; Disease Progression; Endothelium; Estradiol; Event; Failure; Family; Freezing; Gonadal Steroid Hormones; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Hormonal; Hormones; Impairment; Individual; Inflammation; Inflammatory; Lead; Life; Lipids; Liver; Longitudinal Studies; Measures; Mediating; Mendelian randomization; Menopausal Status; Menopause; Menstruation; Metabolic; Metabolic Marker; Movement; Nature; Nuclear Magnetic Resonance; Ovarian aging; Pathway interactions; Peripheral; Phase; Phospholipids; Play; Reporting; Research; Risk Factors; Risk Marker; Role; Specimen; Study of Women' s Health Across the Nation; Testing; Tissues; Translating; Triglycerides; Uncertainty; Visit; Woman; aged; atheroprotective; base; cardioprotection; cardiovascular disorder risk; cohort; epidemiology study; experience; high density lipoprotein receptor; high risk; improved; inflammatory marker; lipoprotein triglyceride; macrophage; middle age; multi-racial; new therapeutic target; novel; oxidation; particle; racial and ethnic; response; reverse cholesterol transport; secondary analysis; systemic inflammatory response; targeted treatment

Title: Compositional and Functional Alterations of HDL Over Ovarian Aging PROJECT SUMMARY This application is in response to the current NIA FOA: PA-17-088 Secondary Analyses of Existing Cohorts, Data Sets and Stored Biospecimens to use data and biospecimens from the Study of Women’s Health Across the Nation (SWAN) to address a critical question about clinical aging, i.e. how ovarian aging impacts the role of high-density lipoproteins (HDL) on risk for cardiovascular disease (CVD). Multiple historic epidemiologic studies reported an inverse association between high-density lipoprotein cholesterol (HDL-C) and CVD, which suggests a direct cardio-protective function of HDL-C. However, recent results from Mendelian randomization studies and the failure of several HDL-C raising agents to reduce CVD risk, cast doubt on a cardio-protective function of HDL-C . As women traverse menopause there appears to be a switch in the direction of the association between HDL-C and CVD risk, with higher HDL-C level being associated with lower CVD risk before menopause and with higher CVD risk after menopause. HDL is a family of heterogeneous subclasses that vary in physico-chemical composition and function. HDL-C only measures the cholesterol load of HDL particles and therefore may not reflect changes in HDL composition and function that could accompany ovarian aging. Metrics of HDL composition and function provide a better ability to reflect the athero-protective features of HDL than HDL-C. Biological changes in these novel metrics of HDL have not been characterized over ovarian aging leading to uncertainty about the impact that the menopausal transition (MT) may have on HDL athero-protective capacity. The MT is a phase of life when women experience an acceleration of subclinical CVD. It is critical to fully understand the nature of the biological changes in HDL that accompany ovarian aging in midlife women. In response to the current NIA FOA: PA-17-088, the current application aims to 1) characterize changes in HDL composition and function over the MT, and assess how changes in HDL composition impact changes in HDL function in women at midlife; 2) evaluate the impacts of hormonal, metabolic and inflammatory marker changes on HDL composition and function changes over the MT; and to explore associations of changes in HDL composition and function with subclinical CVD progression in midlife women and to assess potential pathways. Frozen specimens from women participated in SWAN, a longitudinal study of ovarian aging, will be used to repeatedly measure 1) nuclear magnetic resonance HDL subclasses; 2) HDL content of phospholipids and triglycerides; and 3) the ability of HDL particles to promote cholesterol transport from peripheral cells (HDL-cholesterol efflux capacity), a key cardio-protective function of HDL, over the MT. The combination of the incomparable longitudinal menopause cohort (SWAN) and the comprehensive proposed panel of well-developed HDL composition and function metrics will significantly enhance our understanding of the complex biological changes in HDL over ovarian aging and how these changes could impact early markers of CVD and thus contribute to CVD development in aging women.

标题：HDL对卵巢老化的组成和功能变化 项目摘要 此应用是对当前NIA FOA的响应：PA-17-088现有的二次分析 同类，数据集和存储的生物测量，以研究妇女研究的数据和生物测量 全国的健康（天鹅）解决有关临床衰老的关键问题，即卵巢衰老如何 影响高密度脂蛋白（HDL）对心血管疾病风险（CVD）的作用。多重历史性 流行病学研究报道了高密度脂蛋白胆固醇（HDL-C）之间的逆关联。 和CVD，这表明HDL-C的直接心脏保护功能。但是，来自 孟德尔随机研究和几种HDL-C升高药物降低CVD风险的失败，铸造 怀疑HDL-C的心脏保护功能。当妇女穿越更年期时，似乎有一个开关 在HDL-C和CVD风险之间的关联方向上，HDL-C水平较高 更年期前的CVD风险降低，更年期后CVD风险较高。 HDL是一个家庭 物理化学组成和功能各不相同的异质子类。 HDL-C仅测量 HDL颗粒的胆固醇负荷，因此可能不会反映HDL组成和功能的变化 可以容纳卵巢衰老。 HDL组成和功能的指标提供了更好的反映能力 HDL的动脉保护特征比HDL-C。这些新型HDL指标的生物学变化尚未 在卵巢衰老的特征是导致对更年期过渡的影响的不确定性 （MT）可能具有HDL动脉粥样硬化能力。 MT是女性经历的生活阶段 亚临床CVD的加速度。充分了解HDL生物学变化的性质至关重要 响应当前的NIA FOA：PA-17-088，电流 应用的目的是1）表征MT上HDL组成和功能的变化，并评估如何 HDL组成的变化会影响中年女性HDL功能的变化； 2）评估 HDL组成和功能的变化，在 公吨;并探索HDL组成和功能变化与亚临床CVD进程的关联 在中年妇女并评估潜在途径。来自参加天鹅的妇女的冻结标本 卵巢老化的纵向研究将用于反复测量1）核磁共振HDL 子类； 2）磷脂和甘油三酸酯的HDL含量； 3）HDL颗粒促进的能力 来自外围细胞（HDL-胆固醇外排容量）的胆固醇转运，这是一种关键的心脏保护功能 HDL，在MT上。无与伦比的纵向绝经队列（天鹅）和 发达的HDL组成和功能指标的全面提议的面板将显着 增强我们对HDL对卵巢衰老的复杂生物学变化的理解以及如何 变化可能会影响CVD的早期标记，从而有助于衰老妇女的CVD发展。

项目成果

Pregnancy and Reproductive Risk Factors for Cardiovascular Disease in Women.

• DOI: 10.1161/circresaha.121.319895
• 发表时间: 2022-02-18
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: O'Kelly AC;Michos ED;Shufelt CL;Vermunt JV;Minissian MB;Quesada O;Smith GN;Rich-Edwards JW;Garovic VD;El Khoudary SR;Honigberg MC
• 通讯作者: Honigberg MC

Cardiovascular Disease in Women: Does Menopause Matter?

• DOI: 10.1016/j.coemr.2022.100419
• 发表时间: 2022-12-01
• 期刊: Current opinion in endocrine and metabolic research
• 作者: El Khoudary, Samar R;Nasr, Alexis
• 通讯作者: Nasr, Alexis