Identification of gene signatures regulated by carvedilol in mouse heart

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.

Impact of medication on blood transcriptome reveals off-target regulations of beta-blockers

“…We were not able to compare our results with other studies, because population based gene expression studies for substances have not been published yet. The only study that had analysed the effect of carvedilol on gene expression was for heart tissue in mice [ 32 ]. There was no overlap between the genes found in this study and the genes identified by us.…”

Biased G Protein-Coupled Receptor Signaling: New Player in Modulating Physiology and Pathology

“…Moreover, our group also showed that 7-day infusion of carvedilol induced a unique gene signature on multiple genes related to cardiac disease. Genes upregulated by carvedilol included those encoding proteins in the tight junctions, malaria and viral myocarditis pathway, while downregulated genes were those encoding proteins in the glycosaminoglycan biosynthesis and arrhythmogenic right ventricular cardiomyopathy (Teoh et al ., 2015). These findings make us speculate that carvedilol-responsive miRs can regulate the expression of various detrimental genes to confer cardioprotection (Fig.…”

Transcriptome analysis in heart failure

“…As suggested by the abovementioned studies, detailed mRNA network and pathway analyses can provide substantial insight into the effects of various stimuli on the heart. Such approaches are being used to better understand the beneficial effect of carvedilol treatment, albeit further studies in diseased hearts treated with carvedilol may be required [43]. Meta-analyses of archived RNA-sequencing datasets also promise to uncover similarities and differences between forms of stress-induced cardiac disease, exercise and genetic models, offering mechanistic insight together with suggestions for appropriate therapies [44 & ].…”