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.
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