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Differential coupling of Arg- and Gly389 polymorphic forms of the β₁-adrenergic receptor leads to pathogenic cardiac gene regulatory programs

¹ Cardiopulmonary Genomics Program, University of Maryland School of Medicine, Baltimore, Maryland
² Merck Research Laboratories, Cardiovascular Diseases, Rahway, New Jersey
³ Division of Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, Ohio

The β₁-adrenergic receptor (β₁AR; ADRB1) polymorphism Arg389Gly is located in an intracellular loop and is associated with distinct human and mouse cardiovascular phenotypes. To test the hypothesis that β₁-Arg389 and β₁-Gly389 alleles could differentially couple to pathways beyond that of classic G_s-adenylyl cyclase (AC)/cAMP signaling, we performed comparative gene expression profile analyses on hearts from wild-type and transgenic mice that expressed either human β₁-Arg389 or β₁-Gly389 receptors, or AC5, sampling at an early age prior to the onset of pathological features. All three models upregulated the expression of genes associated with RNA metabolism and translation and downregulated genes associated with mitochondria and energy metabolism, consistent with shared cAMP-driven increase in cardiac contractility, protein synthesis, and compensatory downregulation of mitochondrial energy production. Both β₁AR alleles activated additional genes associated with other pathways. Uniquely, β₁-Arg389 hearts exhibited upregulated expression of genes associated with inflammation, programmed cell death, and extracellular matrix. These observations expand the scope of 7-transmembrane domain receptor signaling propagation beyond known cognate G protein couplings. Moreover, they implicate alterations of a repertoire of processes evoked by a single amino acid variation in the cardiac β₁AR that might be exploited for genotype-specific heart failure diagnostics and therapeutics.

polymorphism; adrenergic; heart failure; β-blocker; microarrays