Beta2-Adrenergic Receptor Gene Variation and Cardiovascular Control in Humans

描述(由申请人提供)：本次A1重新提交的总体目标是促进对人类2-肾上腺素能受体(2-AR)基因单倍型变异和心血管表型的了解。在人类中，2-AR单倍型、对交感兴奋动作(如精神应激和握手)的升压反应、2介导的心脏和血管功能以及饮食中的钠操作之间存在着一种新的但尚未确定的关系。编码2-AR基因第16和第27位氨基酸的单核苷酸多态(SNP)已经被组合表征，但需要检查这三种最常见的单倍型在种族同源队列中的功能相关性，从而控制SNP和种族/民族的变异。我们的策略是针对2-AR单倍型对与高加索人高血压和心血管疾病的发病机制相关的生理和药物反应执行假设驱动的方案。在目标1中，我们测试了2-AR中常见单倍型的纯合个体是否影响正常钠饮食后交感兴奋动作的心血管和局部血管扩张剂反应。我们假设，携带16位甘氨酸(Gly16)和27位谷氨酸(Glu27)纯合单倍型(单倍型1)的健康个体，在精神应激和等长握力运动中，与携带精氨酸(Arg16)+谷氨酰胺(Gln27)(单倍型2)和Gly16+Gln27(单倍型3)单倍型的个体相比，将显示出更大的心输出量和更低的全身血管阻力。在AIM 2中，我们测试了2-AR中常见的单倍型是否影响5天饮食限钠和5天饮食钠负荷后交感兴奋动作的心血管和局部血管扩张剂反应。我们假设，在正常饮食钠摄入量后，单倍型1的心输出量和全身2-AR介导的血管扩张将不再在饮食钠限制后出现，这些反应将在钠负荷后增强。在AIM 3中，我们测试了在压力反射控制循环的暂时药物消融后，2-AR的常见单倍型是否影响全身输注2-AR激动剂的心血管和局部血管扩张剂的反应。我们假设a)在压力感受性反射消融后，单倍型1将比单倍型2和3在全身注射2-AR激动剂时更大的心输出量和更大的2-AR介导的血管扩张；b)2-AR单倍型变异对全身血管阻力的影响将依赖于2-AR介导的一氧化氮的产生。最后，我们假设，体外测定高亲和力结合构象中的淋巴细胞2-AR将从力学上解释饮食钠操作对心血管功能单倍型依赖的差异的影响。这项建议中的机械性高分辨率表型分析将为心血管疾病的发病机制提供重要的新的遗传学见解。 公共卫生相关性 该项目的总体目标是促进对主要心脏和血管受体(β-2肾上腺素能受体)的遗传变异如何影响心血管调节的理解。健康的年轻成年志愿者将根据不同但通常遗传的β-2受体形式进行分组。通过确定应激动作、药物输注和饮食钠摄入量对血压调节的遗传影响，该策略将提供基因如何与与高血压和心血管疾病发展相关的中间生理特征相互作用的机械性细节。

DESCRIPTION (provided by applicant): The overall goal of this A1 resubmission is to advance the understanding of human ¿2-adrenergic receptor (¿2-AR) gene haplotype variation and cardiovascular phenotype. An emerging but yet to be defined relationship exists in humans between ¿2-AR haplotype, the pressor response to sympathoexcitatory maneuvers like mental stress and handgrip, ¿2-mediated cardiac and vascular function, and dietary sodium manipulation. Single nucleotide polymorphisms (SNP's) encoding the 16th and 27th amino acid in the ¿2- AR gene have been characterized in combination, whereas the need exists to examine the functional relevance of the three, most common haplotypes in an ethnically homogenous cohort, thus controlling for variation in SNP's and race/ethnicity. Our strategy is to perform hypothesis-driven protocols with respect to ¿2-AR haplotype on physiological and pharmacological responses pertinent to the pathogenesis of hypertension and cardiovascular disease in Caucasians. In AIM 1 we test whether individuals homozygous for common haplotypes in the ¿2-AR influence the cardiovascular and regional vasodilator responses to sympathoexcitatory maneuvers following a normal sodium diet. We hypothesize that healthy individuals carrying the haplotype homozygous for glycine at position 16 (Gly16) and glutamate at position 27 (Glu27) (haplotype 1) will demonstrate greater cardiac output and lower systemic vascular resistance during mental stress and isometric handgrip exercise than individuals with haplotypes homozygous for arginine (Arg16) + glutamine (Gln27) (haplotype 2) and Gly16 + Gln27 (haplotype 3). In AIM 2 we test whether common haplotypes in ¿2-AR influence the cardiovascular and regional vasodilator responses to sympathoexcitatory maneuvers after 5 days of dietary sodium restriction, followed by 5 days of dietary sodium loading. We hypothesize the greater cardiac output and systemic ¿2-AR mediated vasodilation in haplotype 1 following normal dietary sodium intake will no longer be seen following dietary sodium restriction, and these responses will be augmented following sodium loading. In AIM 3 we test whether common haplotypes in ¿2- AR influence the cardiovascular and regional vasodilator responses to systemic infusions of ¿2-AR agonist, after temporary pharmacological ablation of baroreflex control of the circulation. We hypothesize a) that after baroreflex ablation, the haplotype 1 will be associated with greater cardiac output and greater systemic ¿2-AR mediated vasodilation than haplotypes 2 and 3 during systemic ¿2-AR agonist infusion; b) that effects of ¿2- AR haplotype variation on systemic vascular resistance will be dependent on ¿2-AR mediated production of nitric oxide. Finally, we hypothesize that ex vivo determination of lymphocyte ¿2-AR's present in the high affinity binding conformation will mechanistically explain the influence of dietary sodium manipulation on haplotype-dependent differences in cardiovascular function. The mechanistic high-resolution phenotyping in this proposal will provide important new genetic insight about the pathogenesis of cardiovascular disorders. PUBLIC HEALTH RELEVANCE The overall goal of this project is to advance the understanding of how genetic variation in a major heart and blood vessel receptor (the beta-2 adrenergic receptor) influences cardiovascular regulation. Healthy young adult volunteers will be grouped according to diverse yet commonly inherited forms of the beta-2 receptor. By determining the genetic influence of blood pressure regulation in response to stressful maneuvers, medication infusions, and dietary sodium intake, this strategy will provide mechanistic detail of how genes interact with intermediate physiological traits pertinent to the development of hypertension and cardiovascular disease.