Hypoxia-inducible Transcription Factor 1 (HIF-1) in Vascular Aging

缺氧诱导转录因子 1 (HIF-1) 与血管老化

• 批准号: 7547648
• 负责人: FARZANEH A SOROND
• 金额: $ 10.77万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7547648
• 关键词: Acute; Age; Aging; Aging-Related Process; Animals; Blood Circulation; Blood Flow Velocity; Blood Vessels; Blood flow; Brain Hypoxia-Ischemia; Brain region; Carbon Dioxide; Cells; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Chelating Agents; Chronic; Clinical Trials; Cocoa Powder; Cognitive; Complement; Condition; Congestive Heart Failure; Consumption; Coupling; Data; Deferoxamine; Dementia; Diabetic Angiopathies; Dietary intake; Disease; Doppler Ultrasound; Double-Blind Method; Elderly; Endothelium; Erythropoietin; Failure; Flavonols; Functional disorder; Gene Targeting; Genes; Glucose; Health; Hour; Human; Hypoxia; Impaired cognition; In Vitro; Infusion procedures; Ingestion; Injury; Intake; Iron; Ischemia; Knowledge; Laboratories; Lactate Dehydrogenase; Lactate Dehydrogenases; Link; Measurement; Measures; Mediating; Memory; Mus; Nitric Oxide Synthase; Numbers; Orthostatic Hypotension; Oxygen; Participant; Peripheral; Peripheral Blood Mononuclear Cell; Placebos; Play; Procedures; Process; Proteins; Quercetin; Research Design; Research Personnel; Risk Factors; Role; Serum; Stress; Stroke; Structure of posterior cerebral artery; Syndrome; System; Testing; Tissues; Transcriptional Activation; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular remodeling; Vasodilation; Vasomotor; Work; age related; aged; aging population; attenuation; cerebral artery; cerebrovascular; cobaltous chloride; cognitive function; design; drinking; executive function; functional disability; healthy volunteer; hypoxia inducible factor 1; improved; middle cerebral artery; neuropsychological; placebo controlled study; prevent; programs; response; stem; therapeutic target; transcription factor; volunteer

DESCRIPTION (provided by applicant): Advancing age is associated with a number of geriatric syndromes linked to hypoxic-ischemic injury, such as cerebral microvascular disease, autonomic failure with orthostatic hypotension, stroke, dementia and congestive heart failure. Underlying all of these conditions lies the aging blood vessel, damaged with a dysfunctional endothelium. Potential corrective therapies are unknown. Studies suggest that reduced activation of hypoxia inducible transcription factor-1 (HIF-1) may be involved in age-related vascular dysfunction. HIF-1 is a heterodimeric transcription factor expressed in all tissues in response to hypoxia and ischemia and activates a repertoire of target genes which function to protect oxygen or glucose deprived cells by activating a cassette of cellular, local and systemic responses. In animal studies, pharmacologic augmentation of HIF-1 can reverse age-related decline in HIF-1 activation. However, there have been no prior studies of HIF-1 activation in human aging. There are now two HIF-1 activators available for use in humans-the iron chelator Desferrioxamine (DFO) and a dietary flavonol, quercetin, which can be used to test the effects of acute and chronic HIF-1 activation on the vascular aging process. We have preliminary data to show that the infusion of DFO and the dietary intake of a flavonol-enriched cocoa drink are both associated with a significant cerebral vasodilation and increased cerebral blood flow response in elderly volunteers, as measured by transcranial Doppler ultrasound (TCD). The current proposal will examine the hypothesis that that HIF-1 can be pharmacologically activated in elderly humans and that pharmacologic augmentation of HIF-1 expression can improve age-related changes in cerebrovascular function. Specifically, using a double blind placebo controlled study design, we will compare DFO and quercetin mediated HIF-1 transcriptional activation and cerebrovascular responses in young and elderly healthy volunteers. DFO- and quercetin- mediated HIF-1 activation allows us to examine HIF-1 activation in aging as well as vascular responses to acute and chronic HIF-1 activation in cerebrovascular aging, which have not been previously investigated in humans. The TCD procedures routinely used in our laboratory allow us to assess these hypotheses as they relate to the cerebral arteries of humans, a field in which our knowledge is most deficient. Findings from our study will pave the way for clinical trials of HIF-1 activators in a number of hypoxic-ischemic geritaric disorders, especially cerebrovascular disorders such as ischemia and vascular cognitive impairment, which pose a significant health burden in our aging population.

描述（由申请人提供）：高龄与许多与缺氧缺血性损伤相关的老年综合征相关，如脑微血管疾病、自主神经衰竭伴体位性低血压、中风、痴呆和充血性心力衰竭。所有这些疾病的根源在于血管老化，内皮功能失调。潜在的矫正疗法尚不清楚。研究表明，低氧诱导转录因子-1 （HIF-1）的激活降低可能与年龄相关的血管功能障碍有关。HIF-1是一种异二聚体转录因子，在缺氧和缺血的所有组织中表达，并激活一系列靶基因，通过激活细胞、局部和全身反应来保护缺氧或葡萄糖缺乏的细胞。在动物研究中，药物增强HIF-1可以逆转与年龄相关的HIF-1活性下降。然而，目前还没有关于HIF-1在人类衰老过程中的激活的研究。现在有两种HIF-1激活剂可用于人体——铁螯合剂去铁胺（DFO）和膳食黄酮醇——槲皮素，它们可用于测试急性和慢性HIF-1激活对血管衰老过程的影响。我们有初步的数据表明，经颅多普勒超声（TCD）测量，在老年志愿者中，DFO的输注和富含黄酮醇的可可饮料的饮食摄入都与显著的脑血管舒张和脑血流反应增加有关。