A-Adrenergic Axis in Hypertrophy and Heart Failure

在实验模型中，代偿性肥大的发展及其最终向失代偿性心力衰竭的转变主要由α 1-肾上腺素能受体（AR）和其他Gq转导的信号传导事件介导。反过来，α-和β-肾上腺素能信号传导途径由G-蛋白受体激酶（GRK）和G-蛋白信号传导调节因子（RGS）蛋白调节，其本身在心力衰竭中受到调节，并与其发病机制有关。在先前确定的Gs/Gi偶联肾上腺素能信号传导蛋白遗传风险因素的背景下（项目1），ALLHAT研究结果显示α 1-肾上腺素能受体阻滞剂治疗后心力衰竭发生的个体间差异 提出了这样的假设，即心力衰竭的可变易感性/进展可能是由心脏Gq信号传导的遗传差异引起的。我们的初步研究已经在alpha 1A-AR，RGS 4和GRK 5中发现了8个新的非同义编码多态性（SNPs），并开始建立临床关联和功能扰动。在此，我们将结合辛辛那提和圣安东尼奥心脏研究中受试者的病例对照侵入性和非侵入性研究、小鼠模型中的基因替换以及重组系统中的机制研究，来确定这些SNP与心力衰竭表型之间的病理关联，并建立其作用机制。在特定目标1中，我们将描述人α 1A-AR的非同义SNP对外周血管功能的影响，以及对心肌肥大的发展及其向心力衰竭的进展的影响。在具体目标2中，我们将描述遗传变异GRK 5和RGS 4对心肌收缩力的影响，以及对人类高血压肥大的发展及其向心力衰竭的进展的影响。在具体目标3中，我们将确定α 1A-AR的可变表达的影响， GRKs 2和5，由其各自基因启动子的遗传变异引起，在人类和 实验性心脏肥大和心力衰竭。我们的方法结合了两个独立的心力衰竭人群及其未受影响的对照组中的单等位基因关联研究，基线和压力下综合心血管功能的单基因病例对照分析，以及与项目1合作，对G蛋白偶联受体及其调节蛋白的最常见单倍型的多基因研究。这些研究将导致基于心脏信号单体型的个体化诊断，预防措施和治疗方法。

Development of compensated hypertrophy and its ultimate transition to decompensated heart failure are, in experimental models, largely mediated by alpha1-adrenergic receptor (AR) and other Gq-transduced signaling events. In turn, alpha- and beta- adrenergic signaling pathways are modulated by G-protein Receptor Kinases (GRKs) and Regulators of G-protein Signaling (RGS) proteins, which are themselves regulated in heart failure and have been implicated in its pathogenesis. In the context of previously-established genetic risk factors in Gs/Gi-coupled adrenergic signaling proteins (Project 1), ALLHAT study results showing inter-individual variability in development of heart failure after alpha1-adrenergic receptor blockade suggest the hypothesis that variable susceptibility to/progression of heart failure can be caused by genetic differences in cardiac Gq signaling. Our preliminary studies have identified eight novel non-synonymous coding polymorphisms (SNPs) in alpha1A-AR, RGS4 and GRK5, and begun to establish clinical associations and functional perturbations. Herein, combining case-control invasive and non-invasive studies of subjects in the Cincinnati and San Antonio Heart Studies, gene substitution in mouse models, and mechanistic studies in recombinant systems, we will define the pathological associations between these SNPs and heart failure phenotypes, and establish the mechanisms for their effects. In Specific Aim 1 we will delineate the effects of non-synonymous SNPs of human alpha1A-AR on peripheral vascular function, and on the development of myocardial hypertrophy and its progression to heart failure. In Specific Aim 2 we will delineate the effects of genetically variant GRK5 and RGS4 on cardiac contractility, and on the development of human hypertensive hypertrophy and its progression to heart failure. In Specific Aim 3 we will determine the effects of variable expression of alpha1A-AR and GRKs 2 and 5, caused by genetic variations in their respective gene promoters, on human and experimental cardiac hypertrophy and heart failure. Our approach combines single allele association studies in two independent heart failure populations and their non-affected controls, single-gene case-control analyses of integrated cardiovascular function at baseline and under stress, and in collaboration with Project 1, multi-gene studies of the most common haplotypes for G-protein- coupled receptors and their regulatory proteins. These studies will lead to individualized diagnoses, preventative measures, and therapeutic approaches based on cardiac signaling haplotype.