1. MiR-125b enhances autophagic flux to improve septic cardiomyopathy via targeting STAT3/HMGB1.
- Author
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Yu Y, Ou-Yang WX, Zhang H, Jiang T, Tang L, Tan YF, Luo HY, Xiao ZH, and Li SJ
- Subjects
- Animals, Apoptosis, Cardiomyopathies etiology, Cardiomyopathies metabolism, Cardiomyopathies pathology, Cell Proliferation, HMGB1 Protein genetics, HMGB1 Protein metabolism, Mice, Rats, Rats, Sprague-Dawley, STAT3 Transcription Factor genetics, STAT3 Transcription Factor metabolism, Signal Transduction, Autophagy, Cardiomyopathies prevention & control, HMGB1 Protein antagonists & inhibitors, MicroRNAs genetics, STAT3 Transcription Factor antagonists & inhibitors, Sepsis complications
- Abstract
We explore the role of miR-125b in septic cardiomyopathy, focusing on miR-125b/STAT3/HMGB1 axis. CLP mouse model and LPS-stimulated primary rat cardiomyocytes (CMs) and H9C2 cell were used as in vivo and in vitro models of septic cardiomyopathy, respectively. qRT-PCR and western blot were performed to measure expression levels of miR-125b, STAT3, HMGB1, and autophagy-related proteins. MTT assay was employed to examine LPS toxicity. Dual luciferase activity assay and CHIP were performed to validate interactions of miR-125b/STAT3 and STAT3/HMGB1 promoter. Immunostaining was used to assess the level of autophagic flux. ROS level was measured by fluorescence assay. Heart functions were examined via intracoronary Doppler ultrasound. miR-125b was diminished while STAT3 and HMGB1 were elevated in the heart tissue following CLP surgery and in LPS-treated H9C2 cells. LPS treatment up-regulated ROS generation and suppressed autophagic flux. Overexpression of miR-125b mimics or knockdown of STAT3 or HMGB1 alleviated LPS-induced hindrance of autophagic flux and ROS production. miR-125b directly targeted STAT3 mRNA and STAT3 bound with HMGB1 promoter. Overexpression of miR-125b mitigated myocardial dysfunction induced by CLP in vivo. Hyperactivation of STAT3/HMGB1 caused by reduced miR-125b contributes to ROS generation and the hindrance of autophagic flux during septic cardiomyopathy, leading to myocardial dysfunction., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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