Cardiovascular Consequences of Hypogonadism in Men

 描述(申请人提供)：心血管(CV)老化，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，是心血管疾病(CVD)发展的主要危险因素。男性的衰老与血清睾酮(T)的逐渐和可变的下降有关，而低T与CV的加速老化有关。这个R01提案的目的是确定在低T老年男性中加速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老年男性明显加速CV老化的机制。为了测试这一假设，目标1将使用T正常的年轻男性和老年男性(≥400 ng/dl)和慢性低T老年男性(&lt；300 ng/dl)的横断面比较。在生理盐水(对照组)和系统性抗坏血酸输注(一种显著降低活性氧(ROS)的实验模型)过程中，将测量颈动脉硬度、管道和微血管内皮功能(肱动脉血流介导的扩张、充血峰值速度时间积分和外周动脉测压)以及左室舒张功能指标。此外，还将测量采集的臂动脉和外周静脉内皮细胞以及外周血单核细胞的氧化应激负荷和线粒体功能(生物发生、网络、呼吸、动力学、ROS)。为了更好地将低T的影响从随年龄增长而变化的因素和慢性低T中分离出来，Aim 2将通过评估T正常的老年男性在随机至短期(28 D)性腺抑制(促性腺激素释放激素拮抗剂，GnRHant)+安慰剂(PL)、GnRHant+T或GnRHant+T+芳香化酶抑制剂(AI)前后的心血管功能、氧化应激负荷和线粒体功能的测量来扩展横断面比较。AI将控制T芳构化为雌二醇(E_2)的影响，从而隔离影响，同时抑制E_2，一个强有力的CV功能调节剂。在一个探索性的目标中，将分离臀部皮下脂肪组织小动脉，并评估对乙酰胆碱和针对ROS和线粒体功能的药物(例如抗氧化剂Mito-temol和MitoQ)的内皮血管扩张作用。这项研究的结果将为在细胞和系统水平上调节低T老年男性心血管功能损害的过程提供新的机制。这些研究将有助于更好地理解T在与年龄相关的CV功能变化中的独立作用和作用机制，这将有助于指导未来针对性别的预防CVD的治疗。

 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.