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

Hongfeng Gao,Jixi Yan,Huijing Ma,Aichun Chen,Min Gao,Shujuan Zha

doi:10.1042/bsr20201738

Hongfeng Gao, Jixi Yan + Show 4 more

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https://doi.org/10.1042/bsr20201738

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Abstract

Sepsis is a common cause of deaths of patients in intensive care unit. The study aims to figure out the role of long non-coding RNA (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 microRNA (miRNA)–mRNA network was figured out via an integrative prediction and detection. Myocardial injury was observed by overexpression of high-mobility group box 1 (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 overexpression 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.

Highlights

Sepsis is a deadly organ functional impairment resulting from an imbalance in the body’s reaction to infection [1]
In panels (A,B), n=12, while in panels (C–E) n=6; date are exhibited as mean +− standard deviation (SD); differences between every two groups were analyzed using the independent sample t test, while the differences among multiple groups were analyzed via two-way analysis of variance (ANOVA); **, P
We found that the contents of myocardial injury markers cardiac Troponin I (cTnI) and creatine kinase-MB (CK-MB) in serum were increased in mice following Cecal ligation and puncture (CLP) (Figure 1D), and the levels of tumor necrosis factor-α (TNF-α), IL-6 and IL-1β, and the nitric oxide (NO) content in myocardial tissues were elevated as well (Figure 1E,F)

Summary

Introduction

Sepsis is a deadly organ functional impairment resulting from an imbalance in the body’s reaction to infection [1]. Sepsis takes up 2–6% of all hospital inpatients and accounts for up to 15% of in-hospital mortality, and the mortality is even higher when it is associated with hypotension or hypoperfusion (namely septic shock) [2]. In both developing and developed countries, sepsis is a usual cause of death and brings considerable healthcare burdens [3]. Sepsis usually leads to myocardial dysfunction which is usually defined as sepsis-induced myocardial depression or heart dysfunction, featured with damaged myocardial contractility as well as impaired ejection fraction [5]. 40–50% of patients with septic shock develop different degrees of myocardial depression or dysfunction on their left ventricular ejection fraction, and the mortality of these patients is up to 70%

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