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.

 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.