Long non-coding RNA GAS5 aggravates myocardial depression in mice with sepsis via the microRNA-449b/HMGB1 axis and the NF-κB signaling pathway

Abstract

Sepsis is a common cause of death of patients in intensive care unit. The study aims to figure out the role of lncRNA GAS5 in the myocardial depression in mice with sepsis. Cecal ligation and puncture (CLP) was applied to induce sepsis in mice, and then the heart function, myocardium structure, and the inflammatory response were evaluated. Differentially expressed lncRNAs in mice with sepsis were identified. Then gain- and loss-of-functions of GAS5 were performed in mice to evaluate its role in mouse myocardial depression. The lncRNA-associated miRNA-mRNA network was figured out via an integrative prediction and detection. Myocardial injury was observed by overexpression of HMGB1 in septic mice with knockdown of GAS5 expression. Activity of NF-κB signaling was evaluated, and NF-κB inhibition was induced in mice with sepsis and over-expression of GAS5. Collectively, CLP resulted in myocardial depression and injury, and increased inflammation in mice. GAS5 was highly-expressed in septic mice. GAS5 inhibition reduced myocardial depression, myocardial injury and inflammation responses in septic mice. GAS5 was identified to bind with miR-449b and to elevate HMGB1 expression, thus activating the NF-κB signaling. HMGB1 overexpression or NF-κB inactivation reduced the GAS5-induced myocardial depression and inflammation in septic mice. Our study suggested that GAS5 might promote sepsis-induced myocardial depression via the miR-449b/HMGB1 axis and the following NF-κB activation.

LncRNA GAS5 relates to Th17 cells and serves as a potential biomarker for sepsis inflammation, organ dysfunctions and mortality risk

“…Sepsis is featured by the extremely high mortality which is regarded as a global health priority by the WHO, therefore, it is urgent to find the biomarker involving the development and progression of sepsis to stratify the patients and individualize their treatment, which might help to improve the prognosis of sepsis patients 1–6 . Previous studies have reported the regulation role of lnc‐GAS5 in sepsis 18,24 . For instance, one study shows lnc‐GAS5‑mediated miR‑23a‑3p promotes inflammation and cell apoptosis by targeting TLR4 in a cell model of sepsis.…”

“… 1 , 2 , 3 , 4 , 5 , 6 Previous studies have reported the regulation role of lnc‐GAS5 in sepsis. 18 , 24 For instance, one study shows lnc‐GAS5‑mediated miR‑23a‑3p promotes inflammation and cell apoptosis by targeting TLR4 in a cell model of sepsis. Another study indicates that lnc‐GAS5 aggravates myocardial depression in mice with sepsis via the microRNA‐449b/HMGB1 axis and the NF‐κB signaling pathway.…”

MALAT1 regulates PCT expression in sepsis patients through the miR‐125b/STAT3 axis

“…This means In sepsis studies, LncRNA GAS5 was found to aggravate myocardial inhibitory injury in mice through the microRNA-449B /HMGB1 axis and NF-κB signaling pathway. 18 LncRNA THRIL upregulates TNFα expression through sponge adsorption of miR-19a after upregulation in sepsis, and further damaging human bronchial epithelial cells. 19 LncRNA NEAT1 regulates the NF-κB pathway through competitive binding of miR-204 and affects septic-induced acute kidney injury.…”

High Mobility Group Proteins in Sepsis

“…LncRNA GAS5 could bind to miR-449b and improve the expression of HMGB1, thereby activating NF-κB signal, Gao H et al. found that miR-449b/HMGB1 axis could promote sepsis-induced myocardial inhibition ( 86 ). In sepsis mice model induced by CLP, the expression levels of miR-129-5p and HMGB1 were measured by quantitative real-time polymerase chain reaction and western blot, and the correlation between miR-129-5p and HMGB1 was verified by luciferase assay and RNA immunoprecipitation.…”

“…Down-regulation of lncRNA PVT1 by miRNA-29a/HMGB1 axis attenuates the polarization of macrophage M1 and alleviates sepsis-induced myocardial injury ( 98 ). LncRNA GAS5 might through HMGB1 and subsequent NF-κB promote sepsis-induced myocardial inhibition ( 86 ). LncRNA HOTAIR promotes HK-2 cell apoptosis in sepsis-induced renal injury through HMGB1 ( 99 ).…”