학술논문
An extensive β1-adrenergic receptor gene signaling network regulates molecular remodeling in dilated cardiomyopathies.
Document Type
Academic Journal
Author
Tatman PD; Division of Cardiology, Department of Medicine, and.; Kao DP; Division of Cardiology, Department of Medicine, and.; Colorado Center for Personalized Medicine University of Colorado School of Medicine, Aurora, Colorado, USA.; Chatfield KC; Division of Cardiology, Department of Medicine, and.; Department of Pediatric Cardiology, Children's Hospital Colorado, Aurora, Colorado, USA.; Carroll IA; Division of Cardiology, Department of Medicine, and.; ARCA biopharma, Westminster, Colorado, USA.; Wagner JA; Division of Cardiology, Department of Medicine, and.; Jonas ER; Division of Cardiology, Department of Medicine, and.; Sucharov CC; Division of Cardiology, Department of Medicine, and.; Port JD; Division of Cardiology, Department of Medicine, and.; Lowes BD; Division of Cardiovascular Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.; Minobe WA; Division of Cardiology, Department of Medicine, and.; Huebler SP; ARCA biopharma, Westminster, Colorado, USA.; Karimpour-Fard A; Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, Colorado, USA.; Rodriguez EM; Division of Cardiology, Department of Medicine, and.; Liggett SB; Departments of Medicine and Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.; Bristow MR; Division of Cardiology, Department of Medicine, and.; ARCA biopharma, Westminster, Colorado, USA.
Source
Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE
Subject
Language
English
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.