Cardiometabolic Consequences of the Loss of Ovarian Function

卵巢功能丧失的心脏代谢后果

基本信息

批准号：
10712609
负责人：
Kerrie Moreau
金额：
$ 44.28万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-20 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10712609
关键词：
Abdomen Acceleration Acute Adipocytes Adipose tissue Age Aging Agonist Animals Anti-Inflammatory Agents Antioxidants Area Arteries Attenuated Back Bioenergetics Blood Blood Vessels Body fat Body mass index Cardiovascular Diseases Cell Culture Techniques Chronic Collaborations Colorado Data Development Endocrine Glands Endothelial Cells Endothelium Energy-Generating Resources Environment Enzymes Essential Amino Acids Estradiol Estradiol Antagonists Estrogen Receptor alpha Estrogen deficiency Fatty acid glycerol esters Functional disorder GNRH1 gene Generations Gonadal Hormones Gonadal Steroid Hormones Gonadotropin Hormone Releasing Hormone Health Hormone Antagonists Hormones Human Impairment Inflammatory Intervention Knock-out Knowledge Kynurenic Acid Kynurenine Link Measures Mediating Mediator Menopause Metabolic dysfunction Metabolism Modeling Nicotinamide adenine dinucleotide Nitric Oxide Obesity Ovarian Ovarian Ablation Ovarian hormone Oxidative Stress Participant Pathway interactions Perimenopause Peripheral Placebos Plasma Postmenopause Premenopause Process Production Property Quinolinic Acid Randomized Regulation Research Risk Factors Risk Reduction Role Scientific Advances and Accomplishments Serotonin Serum Signal Pathway Testosterone Tissues Tryptophan Vascular Diseases Vascular Endothelial Cell Vasodilation Visceral Visceral fat Withdrawal Woman abdominal fat adipokines age effect age related brachial artery cardiometabolism cardiovascular disorder risk cytokine endothelial dysfunction gonad function improved insight men new therapeutic target obesogenic older men preclinical study prevent response subcutaneous vascular endothelial dysfunction

项目摘要

PROJECT SUMMARY/ABSTRACT Menopause accelerates cardiovascular disease (CVD) risk due to changes in the hormone environment and adverse changes in cardiometabolic function. The overarching objective of the Colorado SCORE is to advance scientific knowledge of the impact of gonadal aging on the regulation of bioenergetics, abdominal adiposity and cardiometabolic function. We have shown that age-associated vascular endothelial dysfunction, a key antecedent for the development of CVD, is accelerated with gonadal aging in women. We also demonstrated that the menopausal-related decline in estradiol (E2) triggers the development of oxidative stress-mediated endothelial dysfunction. Endothelial function, measured by brachial artery flow- mediated dilation (FMD) decreased with short-term ovarian suppression (via gonadotropin releasing hormone antagonist, GnRHANT) in premenopausal women and this was reversed with E2 add-back. Prior SCORE research demonstrated that long-term ovarian suppression results in a marked increase in abdominal adiposity, particularly visceral, that is prevented by E2. How these adverse changes in adiposity influence vascular aging with E2 deficiency is unknown. Additionally, the mechanisms underlying the increased adiposity and impaired endothelial function in response to the withdrawal of E2 are not completely understood. Emerging evidence links the tryptophan-kynurenine (TRP-KYN) pathway to the regulation of vascular function, adiposity, and the aging process. Our preliminary data in men suggest that increased plasma KYN is associated with increased adiposity and endothelial dysfunction in older men with low testosterone. It is unknown if E2 regulates the TRP-KYN pathway in vascular and adipose tissues. Accordingly, Aim 1 will investigate the impact of increased abdominal visceral adiposity superimposed on the effects of E2 withdrawal on endothelial function. FMD and visceral fat area will be assessed before and after ovarian suppression with randomization to either E2 or placebo add-back. In collaboration with Projects 2 and 3, Aim 2 will determine if tissue-specific alterations in the TRP-KYN pathway are mechanistically linked to increased adiposity and endothelial dysfunction with E2 withdrawal. TRP-KYN metabolites and key enzymes in the pathway will be measured in blood, peripheral vascular endothelial cells, adipose tissue and isolated adipocytes acquired before and after the intervention. In collaboration with Projects 2 and 3, an Exploratory Aim will further examine the mechanistic role of TRP-KYN metabolism with E2 suppression on endothelial function using an ex vivo serum exposure cell culture model and by conducting vasodilation studies of arteries from animals in projects 2 and 3 with varying E2 status. Collectively, Project 1 will provide unique mechanistic insight by which acute and more chronic loss of ovarian function contributes to increased adiposity and endothelial dysfunction and will identify novel therapeutic targets to attenuate/prevent menopause-related cardiometabolic dysfunction and reduce the risk of CVD.

项目概要/摘要由于激素环境的变化和更年期的变化，更年期会加速心血管疾病（CVD）的风险。心脏代谢功能的不良变化。科罗拉多 SCORE 的总体目标是推进关于性腺衰老对生物能量调节影响的科学知识，腹部肥胖和心脏代谢功能。我们已经证明，与年龄相关的血管内皮功能障碍是 CVD 发展的一个关键先决条件，随着性腺老化而加速。女性。我们还证明，与更年期相关的雌二醇 (E2) 下降会引发氧化应激介导的内皮功能障碍。内皮功能，通过肱动脉血流测量介导的扩张（FMD）随着短期卵巢抑制（通过促性腺激素释放激素）而减少拮抗剂，GnRHANT）在绝经前女性中，并且通过 E2 回加可以逆转这一情况。之前的分数研究表明，长期卵巢抑制会导致腹部明显增加 E2 可预防肥胖，尤其是内脏肥胖。肥胖的这些不利变化如何影响 E2 缺乏导致的血管老化尚不清楚。此外，肥胖增加的机制 E2 撤回后内皮功能受损的情况尚不完全清楚。新兴有证据表明色氨酸-犬尿氨酸 (TRP-KYN) 通路与血管功能的调节有关，肥胖和衰老过程。我们在男性中的初步数据表明，血浆 KYN 增加是与睾酮水平较低的老年男性肥胖和内皮功能障碍增加有关。这是尚不清楚 E2 是否调节血管和脂肪组织中的 TRP-KYN 通路。因此，目标 1 将研究腹部内脏脂肪增加对 E2 效果的影响对内皮功能的戒断。卵巢切除前后会评估FMD和内脏脂肪面积通过随机化至 E2 或安慰剂加回进行抑制。与项目 2 和 3 合作，目标 2 将确定 TRP-KYN 通路中的组织特异性改变是否与 E2 停药后肥胖和内皮功能障碍增加。 TRP-KYN 代谢物和关键该途径中的酶将在血液、外周血管内皮细胞、脂肪组织和干预前后获得的分离的脂肪细胞。与项目 2 和 3 合作，探索性目标将进一步研究 TRP-KYN 代谢与 E2 抑制的机制作用使用离体血清暴露细胞培养模型并通过进行血管舒张来观察内皮功能对项目 2 和项目 3 中具有不同 E2 状态的动物的动脉进行研究。总的来说，项目 1 将提供独特的机制见解，急性和更慢性的卵巢功能丧失导致卵巢功能增加肥胖和内皮功能障碍，并将确定新的治疗靶点来减轻/预防更年期相关的心脏代谢功能障碍并降低心血管疾病的风险。