Cardiometabolic Consequences of the Loss of Ovarian Function

卵巢功能丧失的心脏代谢后果

• 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
• 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

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.

项目摘要/摘要 更年期会加速心血管疾病(CVD)的风险，这是由于激素环境和 心脏代谢功能的不良变化。科罗拉多州得分的首要目标是 性腺老化对生物能量学调节的影响的先进科学知识， 腹部肥胖症与心脏代谢功能。我们已经证明了年龄相关的血管 内皮功能障碍是心血管疾病发展的关键前置因素，随着性腺的老化，血管内皮细胞功能障碍加速。 女人。我们还证明，与绝经有关的雌二醇(E_2)的下降会触发发育。 氧化应激介导的内皮功能障碍。内皮功能，通过臂动脉血流来测量- 短期抑制卵巢(通过促性腺激素释放激素)可降低中介扩张(FMD) 拮抗剂，GnRHANT)在绝经前妇女中的作用，这种情况可通过补充E2逆转。之前的分数 研究表明，长期抑制卵巢会导致腹部明显增加 肥胖症，特别是内脏肥胖症，是由雌二醇预防的。肥胖症的这些不利变化如何影响 雌激素缺乏引起的血管衰老尚不清楚。此外，肥胖增加背后的机制 而因E2的退出而导致的内皮功能受损还不完全清楚。新兴 有证据表明色氨酸-犬尿氨酸(Trp-Kyn)途径与血管功能的调节有关， 肥胖症和衰老过程。我们在男性中的初步数据表明，血浆KYN的增加 与低睾酮的老年男性肥胖增加和内皮功能障碍有关。它是 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 探讨腹部内脏肥胖症增加叠加对雌二醇效果的影响 停用血管内皮细胞功能。卵巢前后将评估FMD和内脏脂肪面积 随机化到雌二醇组或安慰剂组的抑制作用。与项目2和项目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 随着E2停用，肥胖和内皮功能障碍增加。色氨酸-KYN代谢物及其关键 该途径中的酶将在血液、外周血管内皮细胞、脂肪组织和 干预前后获得分离的脂肪细胞。在与项目2和3的协作下， 探索性目的将进一步研究抑制E2的Trp-Kyn代谢的机制。 应用体外血清暴露细胞培养模型和血管扩张的内皮功能 对项目2和项目3中不同E2状态的动物的动脉进行研究。总体而言，项目1将提供 独特的机制洞察力，卵巢功能的急性和慢性丧失有助于增加 肥胖和内皮功能障碍，并将确定新的治疗靶点以减轻/预防 更年期相关的心脏代谢功能障碍和降低心血管疾病的风险。