Targeting transcriptional machinery to inhibit enhancer-driven gene expression in heart failure

Rachel A Minerath; Duane D Hall; Chad E Grueter

doi:10.1007/s10741-019-09792-3

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Targeting transcriptional machinery to inhibit enhancer-driven gene expression in heart failure

Journal article

Peer reviewed

Targeting transcriptional machinery to inhibit enhancer-driven gene expression in heart failure

Rachel A Minerath, Duane D Hall and Chad E Grueter

Heart failure reviews, Vol.24(5), pp.725-741

09/2019

DOI: 10.1007/s10741-019-09792-3

PMCID: PMC6698214

PMID: 30972522

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Abstract

Pathological cardiac remodeling is induced through multiple mechanisms that include neurohumoral and biomechanical stress resulting in transcriptional alterations that ultimately become maladaptive and lead to the development of heart failure (HF). Although cardiac transcriptional remodeling is mediated by the activation of numerous signaling pathways that converge on a limited number of transcription factors (TFs) that promote hypertrophy (pro-hypertrophic TFs), the current therapeutic approach to prevent HF utilizes pharmacological inhibitors that largely target specific receptors that are activated in response to pathological stimuli. Thus, there is limited efficacy with the current pharmacological approaches to inhibit transcriptional remodeling associated with the development of HF. Recent evidence suggests that these pro-hypertrophic TFs co-localize at enhancers to cooperatively activate transcription associated with pathological cardiac remodeling. In disease states, including cancer and HF, evidence suggests that the general transcriptional machinery is disproportionately bound at enhancers. Therefore, pharmacological inhibition of transcriptional machinery that integrates pro-hypertrophic TFs may represent a promising alternative therapeutic approach to limit pathological remodeling associated with the development of HF.

Transcription, Genetic - drug effects

Cyclin-Dependent Kinases - metabolism

Humans

Atrial Remodeling - genetics

Heart Failure - genetics

RNA, Long Noncoding - genetics

Transcription Factors - genetics

Molecular Targeted Therapy

Heart Failure - drug therapy

Gene Expression Regulation - drug effects

Transcription Factors - metabolism

Animals

Signal Transduction - drug effects

Ventricular Remodeling - genetics

Mice

Cyclin-Dependent Kinases - antagonists & inhibitors

Cardiomegaly - genetics

RNA, Long Noncoding - metabolism

Cardiomegaly - metabolism

Details

Title: Subtitle: Targeting transcriptional machinery to inhibit enhancer-driven gene expression in heart failure
Creators: Rachel A Minerath - Department of Pharmacology, University of Iowa, Iowa City, IA, 52242, USA
Duane D Hall - Department of Internal Medicine, Division of Cardiovascular Medicine, Francois M. Abboud Cardiovascular Research Center, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, 169 Newton Rd., 4332 PBDB, Iowa City, IA, 52242, USA
Chad E Grueter - Department of Internal Medicine, Division of Cardiovascular Medicine, Francois M. Abboud Cardiovascular Research Center, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, 169 Newton Rd., 4332 PBDB, Iowa City, IA, 52242, USA. chad-grueter@uiowa.edu
Resource Type: Journal article
Publication Details: Heart failure reviews, Vol.24(5), pp.725-741
DOI: 10.1007/s10741-019-09792-3
PMID: 30972522
PMCID: PMC6698214
NLM abbreviation: Heart Fail Rev
ISSN: 1382-4147
eISSN: 1573-7322
Grant note: R01-HL-125436 / NHLBI NIH HHS R01 HL125436 / NHLBI NIH HHS
Language: English
Date published: 09/2019
Academic Unit: Cardiovascular Medicine; Craniofacial Anomalies Research Center; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984094403902771

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