Genetics of In Vivo and In Vitro Endothelial Function in African Americans

描述(由申请人提供)：非裔美国人的外周血管和内皮功能受损，可能是他们高血压患病率高的原因之一。高血压是多种遗传因素和环境因素相互独立、相互作用的结果。有氧运动训练(Extr)通过诱导内皮细胞(EC)因反复暴露于升高的血管切应力而产生适应来纠正内皮功能障碍。然而，在非裔美国人中，运动训练对血管内皮细胞功能的影响和对层流剪切应力(LSS)的EC基因表达反应都是未知的。高生理水平的LSS，例如在有氧运动中发生的那些，会诱导EC基因的表达，这与较低的血压(BP)是一致的。功能基因组中的单核苷酸多态(SNPs)的组合可以解释很大一部分静息BP的可变性和伴随extR的BP变化的可变性。我们将重点介绍EC基因的三个功能群：1)血管活性系统，2)氧化/抗氧化系统，3)切应力信号系统。假设：功能SNPs、先天选择和定位在三个EC功能组的基因将有助于外周血管功能和基线血压，并解释他们对有氧运动训练的反应，这些功能SNPs将与从非裔美国人获得的暴露于LSS的人脐静脉细胞(HUVECs)的差异基因表达有关。其具体目的是：1)确定三个EC功能组的切应力调节基因内的功能SNP是否与切应力/血流介导的扩张(FMD)、前臂绝对血流量(FBFA)以及随ExtR的随意血压和24小时动态血压的变化相关；2)从非裔美国人那里获得具有相同功能SNP的人脐静脉内皮细胞(HUVECs)，以1的特定目的1，将它们暴露在与体内水平相当的LSS中，然后进行基因表达谱分析和RT-PCR以确定是否存在基因表达的基因型依赖差异，3)进行SNP发现。将标准化扰动应用于外周血管系统和内皮细胞，将使我们能够检测遗传效应，这将为高血压的分子生物学外周血管机制提供洞察力。

DESCRIPTION (provided by applicant): Peripheral vasculature and endothelial function are impaired in African Americans and likely contribute to their high prevalence of hypertension. Hypertension results from the independent and interactive effects of multiple genetic and environmental factors. Aerobic exercise training (ExTr) corrects endothelial dysfunction by eliciting adaptations in endothelial cells (EC) due to their repeated exposure to elevated vascular shear stress. However, neither the effects of exercise training on endothelial function nor the EC gene expression response to laminar shear stress (LSS), an in vitro model of exercise, are known in African Americans. High physiological levels of LSS, such as those that occur during aerobic exercise, elicit EC gene expression that is consistent with lower blood pressure (BP). Combinations of single nucleotide polymorphisms (SNPs) in functional genes groups may explain a large portion of the variability in resting BP and in the variability of the changes in BP with ExTr. We will focus on three EC gene functional groups: 1) vasoactive system, 2) oxidant/antioxidant system, and 3) the shear stress signaling system. Hypothesis: functional SNPs, selected apriori and located in genes in the three EC functional groups will contribute to peripheral vascular function and BP at baseline and explain their responses to aerobic exercise training in African American hypertensives, and that these functional SNPs will be related to differential gene expression in human umbilical vein cells (HUVECs) obtained from African Americans and exposed to LSS. The Specific Aims are to: 1) Determine whether functional SNPs within shear stress-regulated genes in the three EC functional groups are associated with changes in shear stress/flow-mediated dilation (FMD), absolute forearm blood flow (FBFA), and changes in casual and 24-hour ambulatory BP with ExTr, 2) Genotype cultured HUVECs obtained from African Americans for the same functional SNPs in Specific Aim 1, expose them to LSS at levels comparable to in vivo levels achieved during aerobic exercise and then perform gene expression profiling and RT-PCR to determine if there are genotype-dependent differences in gene expression, 3) conduct SNP discovery. The application of a standardized perturbation to the peripheral vasculature and ECs, will enable us to detect genetic effects that will provide insights into the molecular biological peripheral vascular mechanisms of hypertension.