miR-146a targets <i>c-Fos</i> expression in human cardiac cells

Palomer, Xavier; Capdevila-Busquets, Eva; Botteri, Gaia; Davidson, Mercy M.; Rodrı́guez, Cristina; Martínez-González, José; Vidal, Francisco; Barroso, Emma; Chan, Tung O.; Feldman, Arthur M.; Vázquez‐Carrera, Manuel

doi:10.1242/dmm.020768

Cited by 38 publications

(39 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…TNFα is also able to induce the expression of miR‐146b‐5p in mature human adipocytes, although this cytokine is more generally known to regulate miR‐146a‐5p expression . However, in none of our liver cell lines, TNFα stimulation led to an increased expression of these miRNAs (except for miR‐146a‐5p in PH5CH8 cells), pointing at a tissue‐ and/or cell type‐specific regulation.…”

Section: Discussionmentioning

confidence: 74%

Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets

Kirchmeyer

Servais

Hamdorf

et al. 2018

Journal of Leukocyte Biology

View full text Add to dashboard Cite

Interleukin-6 (IL-6)-type cytokines play important roles in liver (patho-)biology. For instance, they regulate the acute phase response to inflammatory signals and are involved in hepatocarcinogenesis. Much is known about the regulation of protein-coding genes by cytokines whereas their effects on the miRNome is less well understood. We performed a microarray screen to identify microRNAs (miRNAs) in human hepatocytes which are modulated by IL-6-type cytokines. Using samples of 2 donors, 27 and 68 miRNAs (out of 1,733) were found to be differentially expressed upon stimulation with hyper-IL-6 (HIL-6) for up to 72 h, with an overlap of 15 commonly regulated miRNAs. qPCR validation revealed that miR-146b-5p was also consistently up-regulated in hepatocytes derived from 2 other donors. Interestingly, miR-146b-5p (but not miR-146a-5p) was induced by IL-6-type cytokines (HIL-6 and OSM) in non-transformed liver-derived PH5CH8 and THLE2 cells and in Huh-7 hepatoma cells, but not in HepG2 or Hep3B hepatoma cells. We did not find evidence for a differential regulation of miR-146b-5p expression by promoter methylation, also when analyzing the TCGA data set on liver cancer samples. Inducible overexpression of miR-146b-5p in PH5CH8 cells followed by RNA-Seq analysis revealed effects on multiple mRNAs, including those encoding IRAK1 and TRAF6 crucial for Toll-like receptor signaling. Indeed, LPSmediated signaling was attenuated upon overexpression of miR-146b-5p, suggesting a regulatory loop to modulate inflammatory signaling in hepatocytes. Further validation experiments suggest DNAJC6, MAGEE1, MPHOSPH6, PPP2R1B, SLC10A3, SNRNP27, and TIMM17B to be novel targets for miR-146b-5p (and miR-146a-5p). K E Y W O R D Shepatocarcinogenesis, IL-6-type cytokines, liver, microRNAs, miR-146a-5p steatohepatitis; NF B, nuclear factor kappaB; OSM, oncostatin M; PPP2R1B, protein phosphatase 2 scaffold subunit Abeta; pre-miRNA, precursor-miRNA; pri-miRNA, primary-miRNA; SRPRB, SRP receptor beta subunit; STAT, signal transducer and activator of transcription; TNF , tumor necrosis factor alpha; TRAF6, TNF receptor associated factor 6; TSS, transcription starting site This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

show abstract

Section: Discussionmentioning

confidence: 74%

Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets

Kirchmeyer

Servais

Hamdorf

et al. 2018

Journal of Leukocyte Biology

View full text Add to dashboard Cite

show abstract

“…It has been indicated that the beneficial effects of exosomes are due to its ability to shuttle miRNA between cells [11][12][13][14][15][16]. CDC-XOs contain numerous miRNAs, in particular miR21 and miR146a [18], both of which have been shown to have beneficial effects on the injured myocardium [42][43][44][45][46]. miR21 reduces myocardial apoptosis by modulating expression of programmed cell death 4 (PDCD4), FasL, and AKT pathways [47][48][49].…”

Section: Discussionmentioning

confidence: 99%

Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide

et al. 2018

View full text Add to dashboard Cite

Rationale: Cardiac stem cell-derived exosomes have been demonstrated to promote cardiac regeneration following myocardial infarction in preclinical studies. Recent studies have used intramyocardial injection in order to concentrate exosomes in the infarct. Though effective in a research setting, this method is not clinically appealing due to its invasive nature. We propose the use of a targeting peptide, cardiac homing peptide (CHP), to target intravenously-infused exosomes to the infarcted heart.Methods: Exosomes were conjugated with CHP through a DOPE-NHS linker. Ex vivo targeting was analyzed by incubating organ sections with the CHP exosomes and analyzing with fluorescence microscopy. In vitro assays were performed on neonatal rat cardiomyocytes and H9C2 cells. For the animal study, we utilized an ischemia/reperfusion rat model. Animals were treated with either saline, scramble peptide exosomes, or CHP exosomes 24 h after surgery. Echocardiography was performed 4 h after surgery and 21 d after surgery. At 21 d, animals were sacrificed, and organs were collected for analysis.Results: By conjugating the exosomes with CHP, we demonstrate increased retention of the exosomes within heart sections ex vivo and in vitro with neonatal rat cardiomyocytes. In vitro studies showed improved viability, reduced apoptosis and increased exosome uptake when using CHP-XOs. Using an animal model of ischemia/reperfusion injury, we measured the heart function, infarct size, cellular proliferation, and angiogenesis, with improved outcomes with the CHP exosomes.Conclusions: Our results demonstrate a novel method for increasing delivery of for treatment of myocardial infarction. By targeting exosomes to the infarcted heart, there was a significant improvement in outcomes with reduced fibrosis and scar size, and increased cellular proliferation and angiogenesis.

show abstract

“…Relative levels of specific mRNAs were quantified by real-time RT-PCR as previously described. 45 The sequences of the primers used for amplification are shown in Supplementary Table S2.…”

Section: Histologymentioning

confidence: 99%

SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation

Palomer

Román-Azcona

Pizarro-Delgado

et al. 2020

Sig Transduct Target Ther

Self Cite

121

View full text Add to dashboard Cite

Sirtuin 3 (SIRT3) is a deacetylase that modulates proteins that control metabolism and protects against oxidative stress. Modulation of SIRT3 activity has been proposed as a promising therapeutic target for ameliorating metabolic diseases and associated cardiac disturbances. In this study, we investigated the role of SIRT3 in inflammation and fibrosis in the heart using male mice with constitutive and systemic deletion of SIRT3 and human cardiac AC16 cells. SIRT3 knockout mice showed cardiac fibrosis and inflammation that was characterized by augmented transcriptional activity of AP-1. Consistent with this, SIRT3 overexpression in human and neonatal rat cardiomyocytes partially prevented the inflammatory and profibrotic response induced by TNF-α. Notably, these effects were associated with a decrease in the mRNA and protein levels of FOS and the DNA-binding activity of AP-1. Finally, we demonstrated that SIRT3 inhibits FOS transcription through specific histone H3 lysine K27 deacetylation at its promoter. These findings highlight an important function of SIRT3 in mediating the often intricate profibrotic and proinflammatory responses of cardiac cells through the modulation of the FOS/AP-1 pathway. Since fibrosis and inflammation are crucial in the progression of cardiac hypertrophy, heart failure, and diabetic cardiomyopathy, our results point to SIRT3 as a potential target for treating these diseases.

show abstract

miR-146a targets c-Fos expression in human cardiac cells

Cited by 38 publications

References 49 publications

Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets

Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets

Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide

SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation

Contact Info

Product

Resources

About