Cardiovascular Consequences of Hypogonadism in Men

男性性腺功能减退症的心血管后果

• 批准号: 9206973
• 负责人: Kerrie Moreau
• 金额: $ 56.91万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206973
• 关键词: Acceleration; Acute; Adipose tissue; Age; Aging; Andropause; Antioxidants; Aromatase Inhibitors; Arteries; Ascorbic Acid; Back; Biogenesis; Biological; Biopsy; Blood Vessels; Body Composition; Cardiac health; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Carotid Arteries; Cholinergic Agents; Chronic; Data; Development; Endothelial Cells; Estradiol; Experimental Models; Future; Gel; Gonadotropin Hormone Releasing Hormone; Harvest; Heart; Homeostasis; Hormone Antagonists; Hypogonadism; Impairment; Incidence; Infusion procedures; Intervention; Laboratories; Lead; Left; Measures; Mediating; Menopause; Mitochondria; Modeling; Oxidative Stress; Pathogenesis; Peripheral; Peripheral Blood Mononuclear Cell; Placebos; Play; Prevention therapy; Process; Randomized; Reactive Oxygen Species; Research; Respiration; Risk Factors; Role; Safety; Saline; Serum; Source; Testing; Testosterone; Therapeutic; Time; Vascular Diseases; Vasodilation; Venous; Ventricular; age related; arterial stiffness; arterial tonometry; arteriole; brachial artery; cardiovascular disorder prevention; cardiovascular disorder risk; cardiovascular health; endothelial dysfunction; experimental study; indexing; insight; insulin sensitivity; male; men; men' s group; middle age; mitochondrial dysfunction; mortality; novel therapeutics; older men; prevent; public health relevance; response; sex; subcutaneous; targeted agent; young man

 DESCRIPTION (provided by applicant): Cardiovascular (CV) aging, featuring large artery stiffening, endothelial dysfunction, and impaired left ventricular (LV) diastolic function, is a maor risk factor for the development of cardiovascular diseases (CVD). Male aging is associated with a gradual and variable decline in serum testosterone (T) and low T is associated with accelerated CV aging. The purpose of this R01 proposal is to determine the key functional mechanisms underlying accelerated CV aging in older men with low T. The overall hypothesis is that mitochondrial dysfunction and oxidative stress are mechanisms underlying the apparent accelerated CV aging in older men with low T. To test this hypothesis Aim 1 will use cross-sectional comparisons of young and older men with normal T (≥400 ng/dl), and older men with chronically low T (<300 ng/dl). Carotid artery stiffness, conduit and microvascular endothelial function (brachial artery flow-mediated dilation, hyperemic peak velocity time integral, and peripheral arterial tonometry) and indices of LV diastolic function will be measured during saline (control) and during systemic ascorbic acid infusion, an experimental model to acutely reduce reactive oxygen species (ROS). Additionally, oxidative stress burden and mitochondrial function (biogenesis, networks, respiration, dynamics, ROS) will be measured in harvested brachial artery and peripheral venous endothelial cells, and peripheral blood mononuclear cells. To better isolate the effects of low T from factors that change with aging and chronic low T, Aim 2 will expand on the cross-sectional comparisons by assessing measures of CV function, oxidative stress burden and mitochondrial function in older men with normal T before and after randomization to short-term (28 d) gonadal suppression (gonadotropin releasing hormone antagonist, GnRHant) + placebo (PL), GnRHant+T alone, or GnRHant+T+aromatase inhibitor (AI). AI will control for the effects of aromatization of T to estradiol (E2), and thereby isolate effects while suppressing E2, a potent modulator of CV function. In an exploratory aim, gluteal subcutaneous adipose tissue arterioles will be isolated and assessed for endothelial vasodilation in response to acetylcholine and agents that target ROS and mitochondrial function (e.g., the antioxidants Mito-TEMPOL and MitoQ). The results from this research should provide new mechanistic insight into the processes that mediate the impairment in CV function at the cellular and systemic level in older men with low T. These studies will lead to a better understanding of the independent role of T in age-related changes in CV function and the mechanisms of action, which will help guide future sex-specific therapies for the prevention of CVD.

 描述（由申请人提供）：心血管（CV）衰老，以大动脉硬化、内皮功能障碍和左心室（LV）舒张功能受损为特征，是与男性衰老相关的心血管疾病（CVD）发展的主要危险因素。血清睾酮 (T) 逐渐且可变地下降，且低 T 与加速 CV 老化相关。该 R01 提案的目的是确定低 T 老年男性加速 CV 老化的关键功能机制。总体假设是，线粒体功能障碍和氧化应激是低 T 值老年男性明显加速 CV 老化的潜在机制。为了检验这一假设，目标 1 将使用 T 正常（≥400 ng/dl）的年轻和老年男性的横断面比较) 和长期低 T (<300 ng/dl) 的老年男性，颈动脉硬度、导管和微血管内皮功能（肱动脉血流介导的扩张、充血峰值速度时间）。将在生理盐水（对照）和全身抗坏血酸输注期间测量左室舒张功能指数，这是一种急性降低活性氧（ROS）的实验模型，此外还可以测量氧化应激负担和线粒体功能（将在采集的肱动脉和外周静脉内皮细胞以及外周血单核细胞中测量生物发生、网络、呼吸、动力学、ROS），以更好地分离低 T 的影响。根据随衰老和慢性低 T 变化的因素，目标 2 将通过评估 T 值正常的老年男性在随机分组到短期之前和之后的 CV 功能、氧化应激负担和线粒体功能的测量结果来扩展横断面比较（28 d) 性腺抑制（促性腺激素释放激素拮抗剂，GnRHant）+安慰剂（PL），单独的GnRHant+T，或GnRHant+T+芳香酶抑制剂（AI）将控制效果。 T 芳香化为雌二醇 (E2)，并由此分离效应，同时抑制 E2（CV 功能的有效调节剂）。在一项探索性目标中，将分离臀肌皮下脂肪组织小动脉，并评估乙酰胆碱和靶向药物的内皮血管舒张作用。 ROS 和线粒体功能（例如抗氧化剂 Mito-TEMPOL 和 MitoQ）。这项研究的结果应该提供新的结果。深入了解低 T 的老年男性在细胞和系统水平上介导 CV 功能损伤的过程。这些研究将有助于更好地理解 T 在 CV 功能年龄相关变化中的独立作用及其机制行动，这将有助于指导未来预防 CVD 的性别特异性疗法。