MicroRNA-125b Prevents Cardiac Dysfunction in Polymicrobial Sepsis by Targeting TRAF6-Mediated Nuclear Factor κB Activation and p53-Mediated Apoptotic Signaling

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Abstract

This study examined the effect of microRNA-125b (miR-125b) on sepsis-induced cardiac dysfunction.

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Epidemiology of severe sepsis

Florian Mayr, Sachin Yende, Derek C Angus (2013)

Severe sepsis is a leading cause of death in the United States and the most common cause of death among critically ill patients in non-coronary intensive care units (ICU). Respiratory tract infections, particularly pneumonia, are the most common site of infection, and associated with the highest mortality. The type of organism causing severe sepsis is an important determinant of outcome, and gram-positive organisms as a cause of sepsis have increased in frequency over time and are now more common than gram-negative infections. Recent studies suggest that acute infections worsen pre-existing chronic diseases or result in new chronic diseases, leading to poor long-term outcomes in acute illness survivors. People of older age, male gender, black race, and preexisting chronic health conditions are particularly prone to develop severe sepsis; hence prevention strategies should be targeted at these vulnerable populations in future studies.

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MicroRNA-125b is a novel negative regulator of p53.

Minh Le, Cathleen Teh, Ng Shyh-Chang … (2009)

The p53 transcription factor is a key tumor suppressor and a central regulator of the stress response. To ensure a robust and precise response to cellular signals, p53 gene expression must be tightly regulated from the transcriptional to the post-translational levels. Computational predictions suggest that several microRNAs are involved in the post-transcriptional regulation of p53. Here we demonstrate that miR-125b, a brain-enriched microRNA, is a bona fide negative regulator of p53 in both zebrafish and humans. miR-125b-mediated down-regulation of p53 is strictly dependent on the binding of miR-125b to a microRNA response element in the 3' untranslated region of p53 mRNA. Overexpression of miR-125b represses the endogenous level of p53 protein and suppresses apoptosis in human neuroblastoma cells and human lung fibroblast cells. In contrast, knockdown of miR-125b elevates the level of p53 protein and induces apoptosis in human lung fibroblasts and in the zebrafish brain. This phenotype can be rescued significantly by either an ablation of endogenous p53 function or ectopic expression of miR-125b in zebrafish. Interestingly, miR-125b is down-regulated when zebrafish embryos are treated with gamma-irradiation or camptothecin, corresponding to the rapid increase in p53 protein in response to DNA damage. Ectopic expression of miR-125b suppresses the increase of p53 and stress-induced apoptosis. Together, our study demonstrates that miR-125b is an important negative regulator of p53 and p53-induced apoptosis during development and during the stress response.

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The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs.

Ariadne Androulidaki, Dimitrios Iliopoulos, Alicia Arranz … (2009)

MicroRNAs regulated by lipopolysaccharide (LPS) target genes that contribute to the inflammatory phenotype. Here, we showed that the protein kinase Akt1, which is activated by LPS, positively regulated miRNAs let-7e and miR-181c but negatively regulated miR-155 and miR-125b. In silico analyses and transfection studies revealed that let-7e repressed Toll-like receptor 4 (TLR4), whereas miR-155 repressed SOCS1, two proteins critical for LPS-driven TLR signaling, which regulate endotoxin sensitivity and tolerance. As a result, Akt1(-/-) macrophages exhibited increased responsiveness to LPS in culture and Akt1(-/-) mice did not develop endotoxin tolerance in vivo. Overexpression of let-7e and suppression of miR-155 in Akt1(-/-) macrophages restored sensitivity and tolerance to LPS in culture and in animals. These results indicate that Akt1 regulates the response of macrophages to LPS by controlling miRNA expression.

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Journal

Title: Journal of Infectious Diseases

Abbreviated Title: J Infect Dis.

Publisher: Oxford University Press (OUP)

ISSN (Print): 0022-1899

ISSN (Electronic): 1537-6613

Publication date Created: November 14 2016

Publication date Created: December 01 2016

Publication date (Print): December 01 2016

Publication date (Electronic): September 28 2016

Volume: 214

Issue: 11

Pages: 1773-1783

Article

DOI: 10.1093/infdis/jiw449

PMC ID: 5144735

PubMed ID: 27683819

SO-VID: ae357ec3-9f72-47ae-9c96-1cfa36887c56

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MicroRNA-125b Prevents Cardiac Dysfunction in Polymicrobial Sepsis by Targeting TRAF6-Mediated Nuclear Factor κB Activation and p53-Mediated Apoptotic Signaling

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Abstract

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Neuronal Signaling

Most cited references 31

Epidemiology of severe sepsis

MicroRNA-125b is a novel negative regulator of p53.

The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs.

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Cited by 36

Most referenced authors 588