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Physiol Genomics. 2015 Sep;47(9):376-85. doi: 10.1152/physiolgenomics.00028.2015. Epub 2015 Jul 7.

Identification of gene signatures regulated by carvedilol in mouse heart.

Author information

  • 1Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia;
  • 2Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia; and.
  • 3Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia; Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia;
  • 4Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia;
  • 5Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia; and.
  • 6Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia ilkim@gru.edu.

Abstract

Chronic treatment with the β-blocker carvedilol has been shown to reduce established maladaptive left ventricle (LV) hypertrophy and to improve LV function in experimental heart failure. However, the detailed mechanisms by which carvedilol improves LV failure are incompletely understood. We previously showed that carvedilol is a β-arrestin-biased β1-adrenergic receptor ligand, which activates cellular pathways in the heart independent of G protein-mediated second messenger signaling. More recently, we have demonstrated by microRNA (miR) microarray analysis that carvedilol upregulates a subset of mature and pre-mature miRs, but not their primary miR transcripts in mouse hearts. Here, we next sought to identify the effects of carvedilol on LV gene expression on a genome-wide basis. Adult mice were treated with carvedilol or vehicle for 1 wk. RNA was isolated from LV tissue and hybridized for microarray analysis. Gene expression profiling analysis revealed a small group of genes differentially expressed after carvedilol treatment. Further analysis categorized these genes into pathways involved in tight junction, malaria, viral myocarditis, glycosaminoglycan biosynthesis, and arrhythmogenic right ventricular cardiomyopathy. Genes encoding proteins in the tight junction, malaria, and viral myocarditis pathways were upregulated in the LV by carvedilol, while genes encoding proteins in the glycosaminoglycan biosynthesis and arrhythmogenic right ventricular cardiomyopathy pathways were downregulated by carvedilol. These gene expression changes may reflect the molecular mechanisms that underlie the functional benefits of carvedilol therapy.

KEYWORDS:

beta-blocker; biased G protein-coupled receptor signaling; gene regulation; left ventricle; transcriptome

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