Beta2-Adrenergic Receptor Gene Variation and Cardiovascular Control in Humans

描述（由申请方提供）：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理解。在人类中，<$2-AR单倍型、对交感神经兴奋性操作（如精神压力和握力）的升压反应、<$2介导的心脏和血管功能以及膳食钠操作之间存在一种新兴但尚未确定的关系。编码Δ 2- AR基因中的第16和第27个氨基酸的单核苷酸多态性（SNP）已被组合表征，而需要检查在种族同质群组中三种最常见的单倍型的功能相关性，从而控制SNP和种族/民族的变异。我们的策略是对与高加索人高血压和心血管疾病发病机制相关的生理和药理反应进行关于2-AR单倍型的假设驱动方案。在AIM 1中，我们测试了在正常钠饮食后，<$2-AR中常见单倍型纯合子的个体是否影响心血管和局部血管舒张剂对交感神经兴奋性动作的反应。我们假设健康个体携带单倍型16位甘氨酸（Gly 16）和27位谷氨酸（Glu 27）纯合子，（单倍型1）在精神应激和等长握力运动中比精氨酸（Arg 16）+谷氨酰胺（Gln 27）单倍型纯合的个体表现出更大的心输出量和更低的全身血管阻力Gly 16 + Gln 27（单倍型3）。在AIM 2中，我们测试了在饮食钠限制5天后，继之以饮食钠负荷5天后，<$2-AR中常见的单倍型是否影响心血管和局部血管舒张剂对交感神经兴奋性动作的反应。我们假设在单倍型1中，在正常饮食钠摄入后，更大的心输出量和全身性<$2-AR介导的血管舒张在饮食钠限制后将不再出现，并且这些反应在钠负荷后将增强。在AIM 3中，我们测试了在暂时药理学消融循环的压力反射控制后，<$2- AR中的常见单倍型是否影响对<$2-AR激动剂全身输注的心血管和局部血管舒张反应。我们假设：a）在压力反射消融后，在全身性<$2-AR激动剂输注期间，单倍型1将与单倍型2和3相比更大的心输出量和更大的全身性<$2-AR介导的血管舒张相关; B）<$2- AR单倍型变异对全身血管阻力的影响将依赖于<$2-AR介导的一氧化氮产生。最后，我们假设，离体测定淋巴细胞<$2-AR的存在于高亲和力结合构象将机械地解释影响饮食钠操纵单倍型依赖性的心血管功能的差异。该机制的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β-2受体的不同但常见的遗传形式进行分组。通过确定血压调节的遗传影响，以应对压力演习，药物输注，和饮食中的钠摄入量，这一策略将提供基因如何与中间生理性状相关的高血压和心血管疾病的发展相互作用的机制细节。

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.