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

Abstract

Swift SM, Gaume BR, Small KM, Aronow BJ, Liggett SB. Differential coupling of Arg-and Gly389 polymorphic forms of the ␤1-adrenergic receptor leads to pathogenic cardiac gene regulatory programs.

Temporal analysis of mRNA and miRNA expression in transgenic mice overexpressing Arg- and Gly389 polymorphic variants of the β1-adrenergic receptor

“…These analyses show that in ␤ 1 -Arg389 mice, at either 3 or 6 -8 mo, a substantial number of genes are uniquely up-or downregulated, a result concordant with the previous gene expression study performed in 3 mo ␤ 1 -Arg389 vs. Gly overexpressor animals (27). In contrast, the majority of regulated genes in Gly389 mice are also regulated in Arg389 overexpressors.…”

“…However, only early time points were characterized in that study. The main difference between the current study and the Swift et al study (27) is that the previous study focused on gene expression changes at an early, "preclinical" time point, and between-genotype comparison of gene expression changes and their relationship to cAMP/PKA pathways. The current study analyzes changes in gene expression over time as disease progresses and compares these changes between genotypes to determine if the changes observed at an early stage are related to genotype (Arg or Gly) or to the subsequent development of a cardiomyopathy and LV dysfunction.…”

“…Previously, Swift et al (27) have analyzed gene expression changes in 3 mo old ␤ 1 -Arg389, ␤ 1 -Gly389, and adenylyl cyclase 5 (AC5) transgenic animals. The authors identified a set of genes and pathways uniquely regulated at early stages of ␤ 1 -Arg389 overexpression, prior to the onset of myocardial disease.…”

“…To investigate these differences, Swift at al. (27) performed genomewide mRNA expression profiling in 3 mo old transgenic mice overexpressing each of the ␤ 1 389 AR variants. Overexpression of the ␤ 1 -Arg389 variant resulted in a greater number of uniquely regulated genes that were specific to apoptosis, inflammation and extracellular matrix (27) categories.…”

“…(27) performed genomewide mRNA expression profiling in 3 mo old transgenic mice overexpressing each of the ␤ 1 389 AR variants. Overexpression of the ␤ 1 -Arg389 variant resulted in a greater number of uniquely regulated genes that were specific to apoptosis, inflammation and extracellular matrix (27) categories. This observation suggests that ␤ 1 -Arg and Gly389 ARs may access different downstream signaling pathways, i.e., that there may be qualitative differences in post receptor signaling between the two receptor variants that have pathophysiologic implications.…”