Abstract
We investigated the extent, biologic characterization, phenotypic specificity, and possible regulation of a β1-adrenergic receptor–linked (β1-AR–linked) gene signaling network (β1-GSN) involved in left ventricular (LV) eccentric pathologic remodeling. A 430-member β1-GSN was identified by mRNA expression in transgenic mice overexpressing human β1-ARs or from literature curation, which exhibited opposite directional behavior in interventricular septum endomyocardial biopsies taken from patients with beta-blocker–treated, reverse remodeled dilated cardiomyopathies. With reverse remodeling, the major biologic categories and percentage of the dominant directional change were as follows: metabolic (19.3%, 81% upregulated); gene regulation (14.9%, 78% upregulated); extracellular matrix/fibrosis (9.1%, 92% downregulated); and cell homeostasis (13.3%, 60% upregulated). Regarding the comparison of β1-GSN categories with expression from 19,243 nonnetwork genes, phenotypic selection for major β1-GSN categories was exhibited for LV end systolic volume (contractility measure), ejection fraction (remodeling index), and pulmonary wedge pressure (wall tension surrogate), beginning at 3 months and persisting to study completion at 12 months. In addition, 121 lncRNAs were identified as possibly involved in cis-acting regulation of β1-GSN members. We conclude that an extensive 430-member gene network downstream from the β1-AR is involved in pathologic ventricular remodeling, with metabolic genes as the most prevalent category.
Authors
Philip D. Tatman, David P. Kao, Kathryn C. Chatfield, Ian A. Carroll, Jessica A. Wagner, Eric R. Jonas, Carmen C. Sucharov, J. David Port, Brian D. Lowes, Wayne A. Minobe, Sophia P. Huebler, Anis Karimpour-Fard, Erin M. Rodriguez, Stephen B. Liggett, Michael R. Bristow
Figure 2
GO pathway enrichment of the β1 gene signaling network in reverse-remodeled human left ventricles.
