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

描述(申请人提供)：高龄与许多与缺氧缺血性损伤有关的老年综合征有关，如脑微血管疾病、自主性低血压、中风、痴呆症和充血性心力衰竭。在所有这些情况下，是老化的血管，内皮功能失调而受损。潜在的矫正疗法尚不清楚。研究表明，缺氧诱导转录因子-1(HIF-1)活性降低可能参与了老年性血管功能障碍。HIF-1是一种异源二聚体转录因子，在所有组织中表达，对缺氧和缺血做出反应，并激活一系列靶基因，这些基因通过激活一盒细胞、局部和全身反应来保护缺氧或葡萄糖缺乏的细胞。在动物实验中，HIF-1的药物增强可以逆转与年龄相关的HIF-1活性的下降。然而，此前还没有关于HIF-1激活在人类衰老中的研究。现在有两种HIF-1激动剂可供人类使用-铁络合剂去铁胺(DFO)和饮食中的黄酮醇-栎素，可用于测试急性和慢性HIF-1激活对血管衰老过程的影响。我们有初步数据表明，根据经颅多普勒超声(TCD)的测量，服用DFO和饮食中摄入富含黄酮醇的可可饮料都与老年志愿者显著的脑血管扩张和脑血流反应增加有关。 目前的建议将检验这样的假设，即HIF-1在老年人中可以被药物激活，并且药物增强HIF-1的表达可以改善与年龄相关的脑血管功能变化。具体地说，采用双盲安慰剂对照研究设计，我们将在年轻和老年健康志愿者中比较DFO和槲皮素介导的HIF-1转录激活和脑血管反应。DFO和Quercetin介导的HIF-1激活使我们能够检测衰老过程中的HIF-1激活，以及脑血管衰老过程中血管对急性和慢性HIF-1激活的反应，这在以前还没有在人类中进行过研究。我们实验室中常规使用的经颅多普勒检查程序使我们能够评估这些假说，因为它们与人类的大脑动脉有关，而这是我们知识最缺乏的一个领域。我们的研究结果将为HIF-1激活剂在一些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，如缺血和血管认知障碍，这些疾病在我们老龄化的人口中构成了巨大的健康负担。

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.