Human antigen R as a therapeutic target in pathological cardiac hypertrophy

Green, Lisa C; Anthony, Sarah; Slone, Samuel; Lanzillotta, Lindsey; Nieman, Michelle L.; Wu, Xiaoqing; Robbins, Nathan; Jones, Shannon; Roy, Sudeshna; Owens, A. Phillip; Aubé, Jeffrey; Xu, Liang; Lorenz, John N.; Blaxall, Burns C.; Rubinstein, Jack; Benoit, Joshua B.; Tranter, Michael

doi:10.1172/jci.insight.121541

Cited by 42 publications

(49 citation statements)

References 31 publications

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“…RNA was isolated from BAT as previously described [15] and poly(A) library preparation and sequencing were done by the CCHMC DNA sequencing and genotyping core. Sequence read mapping, principal component analysis, differential expression analysis, heat mapping, and generation of volcano plots were done using CLC Genomics Workbench (v. 20.0.2, Qiagen) as previously described [16]. The statistical significance threshold for expression between groups was defined as an FDR-corrected P-value less than or equal to 0.05 and a fold-change greater than or equal to 1.5.…”

Section: Rna-seq Analysismentioning

confidence: 99%

HuR expression in adipose tissue mediates energy expenditure and acute thermogenesis independent of UCP1 expression

et al. 2020

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The goal of this study was to define the functional role of adipocyte-specific expression of the RNA binding protein Human antigen R (HuR). Mice with an adipocyte-specific deletion of HuR (Adipo-HuR −/-) were generated by crossing HuR floxed (HuR fl/fl) mice with mice expressing adiponectin-driven cre-recombinase (Adipoq-cre). Our results show that Adipo-HuR −/mice display a lean phenotype compared to wild-type littermate controls. HuR deletion results in a diet-independent reduction in percent body fat composition along with an increase in energy expenditure. Functionally, Adipo-HuR −/mice show a significant impairment in acute adaptive thermogenesis (six hours at 4°C), but uncoupling protein 1 (UCP1) protein expression in brown adipose tissue (BAT) is unchanged compared to control. Pharmacological inhibition of HuR also results in a marked decline in core body temperature following acute cold challenge independent of UCP1 protein expression. Among the 588 HuR-dependent genes in BAT identified by RNA-seq analysis, gene ontology analysis shows a significant enrichment in mediators of calcium transport and signalling, almost all of which are decreased in Adipo-HuR −/mice compared to control. In conclusion, adipocyte expression of HuR plays a central role in metabolic homoeostasis and mediates UCP1-independent thermogenesis in BAT, potentially through post-transcriptional control of intracellular calcium transport.

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Section: Rna-seq Analysismentioning

confidence: 99%

HuR expression in adipose tissue mediates energy expenditure and acute thermogenesis independent of UCP1 expression

et al. 2020

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“…HuR activity is negligible in normal adult hearts, and thus cardiomyocyte specific deletion does not affect basal cardiac function, yet HuR deletion does reduce hypertrophy and cardiac functional decline in response to TAC. Importantly, the authors report clinical benefits from pharmacological HuR inhibition even when hypertrophy is already detectable [82].…”

Section: Au-rich Element Binding Proteinsmentioning

confidence: 95%

“…Elevation of inflammatory cytokines during cardiac hypertrophy has recently been observed to, at least partially, rely on translation of inflammatory genes mediated by enhanced stability of their mRNA by ARE-RNA binding proteins. The increase in ARE binding protein activity during the progression to heart failure is accompanied by their translocation from the nucleus to the cytoplasm [81,82]. One example of an ARE binding protein induced during human heart failure and in a mouse model of TAC induced pressure overload is brain-expressed X-linked protein 1 (BEX1).…”

Section: Au-rich Element Binding Proteinsmentioning

confidence: 99%

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Translating Translation to Mechanisms of Cardiac Hypertrophy

Zeitz

Smyth

2020

JCDD

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Cardiac hypertrophy in response to chronic pathological stress is a common feature occurring with many forms of heart disease. This pathological hypertrophic growth increases the risk for arrhythmias and subsequent heart failure. While several factors promoting cardiac hypertrophy are known, the molecular mechanisms governing the progression to heart failure are incompletely understood. Recent studies on altered translational regulation during pathological cardiac hypertrophy are contributing to our understanding of disease progression. In this brief review, we describe how the translational machinery is modulated for enhanced global and transcript selective protein synthesis, and how alternative modes of translation contribute to the disease state. Attempts at controlling translational output through targeting of mTOR and its regulatory components are detailed, as well as recently emerging targets for pre-clinical investigation.

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“…While HuR increases the activity of pro-inflammatory genes like TNF-α, it also decreases the activity of anti-inflammatory genes like eNOS, a classical example of reciprocal regulation of different genes by the same ARE-BP to achieve maximal activation of pro-inflammatory immunogenic pathways [52]. Importantly, misregulation of HuR has also been shown to contribute to cardiac arrhythmias, fibrosis, and pathogenic remodeling during HF [53,54]. This further supports the idea that ARE misregulation can lead to cardiovascular damage.…”

Section: Au-rich Elementsmentioning

confidence: 99%

Cardiovascular inflammation: RNA takes the lead

Martens

Bansal

Accornero

2019

Journal of Molecular and Cellular Cardiology

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Inflammation has recently gained tremendous attention as a key contributor in several chronic diseases. While physiological inflammation is essential to counter a wide variety of damaging stimuli and to improve wound healing, dysregulated inflammation such as in the myocardium and vasculature can promote cardiovascular diseases. Given the high severity, prevalence, and economic burden of these diseases, understanding the factors involved in the regulation of physiological inflammation is essential. Like other complex biological phenomena, RNA-based processes are emerging as major regulators of inflammatory responses. Among such processes are cis-regulatory elements in the mRNA of inflammatory genes, noncoding RNAs directing the production or localization of inflammatory cytokines/chemokines, or pathogenic RNA driving inflammatory responses. In this review, we describe several specific RNA-based molecular mechanisms by which physiological inflammation pertaining to cardiovascular diseases is regulated. These include the role of AU-rich element-containing mRNAs, long non-coding RNAs, microRNAs, and viral RNAs.

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Human antigen R as a therapeutic target in pathological cardiac hypertrophy

Cited by 42 publications

References 31 publications

HuR expression in adipose tissue mediates energy expenditure and acute thermogenesis independent of UCP1 expression

HuR expression in adipose tissue mediates energy expenditure and acute thermogenesis independent of UCP1 expression

Translating Translation to Mechanisms of Cardiac Hypertrophy

Cardiovascular inflammation: RNA takes the lead

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