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

描述（由申请人提供）：年龄增长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、自主神经功能衰竭伴直立性低血压、卒中、痴呆和充血性心力衰竭。所有这些疾病的基础是血管老化，内皮功能障碍。潜在的纠正治疗尚不清楚。研究表明，低氧诱导转录因子-1（HIF-1）的活化减少可能参与了年龄相关的血管功能障碍。HIF-1是一种在所有组织中表达的异二聚体转录因子，其响应于缺氧和缺血，并激活靶基因库，所述靶基因库通过激活细胞、局部和全身反应的盒来保护缺氧或缺糖细胞。在动物研究中，HIF-1的药理学增强可以逆转HIF-1活化的年龄相关性下降。然而，以前没有研究过HIF-1在人类衰老中的激活。现在有两种HIF-1激活剂可用于人类-铁螯合剂Desferrioxamine（DFO）和膳食黄酮醇槲皮素，可用于测试急性和慢性HIF-1激活对血管老化过程的影响。我们有初步数据表明，DFO的输注和富含黄酮醇的可可饮料的饮食摄入都与老年志愿者的显著脑血管舒张和脑血流反应增加有关，如经颅多普勒超声（TCD）所测量的。 目前的建议将检查的假设，即HIF-1可以在老年人中被激活，并且HIF-1表达的药理学增强可以改善脑血管功能的年龄相关变化。具体而言，使用双盲安慰剂对照研究设计，我们将比较年轻和老年健康志愿者中DFO和槲皮素介导的HIF-1转录激活和脑血管反应。DFO和槲皮素介导的HIF-1激活使我们能够检查衰老中的HIF-1激活以及脑血管衰老中对急性和慢性HIF-1激活的血管反应，这在人类中以前没有研究过。我们实验室常规使用的TCD程序使我们能够评估这些假设，因为它们与人类的脑动脉有关，这是我们知识最缺乏的领域。我们的研究结果将为HIF-1激活剂在许多缺氧缺血性老年性疾病中的临床试验铺平道路，特别是脑血管疾病，如缺血和血管性认知障碍，这对我们的老龄化人口构成了重大的健康负担。

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.