title: miR-21-3p controls sepsis-associated cardiac dysfunction via regulating SORBS2.
abstract: Cardiac dysfunction with sepsis is a major cause of death in intensive care units. Several lines of evidence have revealed the potential of microRNAs (miRNAs, miRs) as biomarkers for detecting sepsis, though direct evidence of their functional roles in septic cardiac dysfunction is still lacking. In this study, C57BL/6 mice were exposed to lipopolysaccharide (LPS) to induce sepsis-associated cardiac dysfunction, as evidenced by reduced fractional shortening (FS) and ejection fraction (EF) and detrimental changes in cardiac contractility, inflammation, and energy metabolism. Microarray analysis and qRT-PCRs revealed that miR-21-3p was significantly induced in heart samples challenged with LPS. Impressively, pharmacological inhibition of miR-21-3p using antagomiR was able to preserve FS and EF and prevent mitochondria ultrastructural damage and autophagy in LPS-treated mice, while forced expression of miR-21-3p using agomiR aggravated that. Besides that, miR-21-3p antagomiR improved the survival of mice treated with LPS. Meanwhile, our data showed that SH3 domain-containing protein 2 (SORBS2) was inversely correlated with miR-21-3p expression level in mice hearts, and was repressed in hearts challenged with LPS, suggesting SORBS2 as a target gene of miR-21-3p. Additionally, plasma miR-21-3p was markedly elevated in septic patients with cardiac dysfunction as compared to septic patients without cardiac dysfunction. The ROC curve showed that plasma miR-21-3p could be a specific predictor of septic patients developing cardiac dysfunction with an area under the curve of 0.939. Collectively, the present study provides strong evidence that miR-21-3p controls sepsis-associated cardiac dysfunction via regulating SORBS2. Inhibition of miR-21-3p might be a protective strategy to treat sepsis-induced cardiac dysfunction.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Regeneration and Ageing Lab, Experimental Center of Life Sciences, School of Life Science, Shanghai University, Shanghai 200444, China; Innovative Drug Research Center of Shanghai University, Shanghai 200444, China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Bei
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Shutong
authors.initials: S
authors.lastname: Shen
authors.affiliation: Department of Emergency, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Peipei
authors.initials: P
authors.lastname: Huang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jialiang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Regeneration and Ageing Lab, Experimental Center of Life Sciences, School of Life Science, Shanghai University, Shanghai 200444, China; Innovative Drug Research Center of Shanghai University, Shanghai 200444, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Regeneration and Ageing Lab, Experimental Center of Life Sciences, School of Life Science, Shanghai University, Shanghai 200444, China; Innovative Drug Research Center of Shanghai University, Shanghai 200444, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Regeneration and Ageing Lab, Experimental Center of Life Sciences, School of Life Science, Shanghai University, Shanghai 200444, China; Innovative Drug Research Center of Shanghai University, Shanghai 200444, China.
authors.forename: Tianzhao
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. Electronic address: xiangqingkong_nj@163.com.
authors.forename: Xiangqing
authors.initials: X
authors.lastname: Kong
authors.affiliation: Regeneration and Ageing Lab, Experimental Center of Life Sciences, School of Life Science, Shanghai University, Shanghai 200444, China; Innovative Drug Research Center of Shanghai University, Shanghai 200444, China. Electronic address: junjiexiao@shu.edu.cn.
authors.forename: Junjie
authors.initials: J
authors.lastname: Xiao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002470:Cell Survival / Q000235:genetics; D004734:Energy Metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics*; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D034622:RNA Interference; D016601:RNA-Binding Proteins; D012372:ROC Curve; D051381:Rats; D018805:Sepsis / Q000150:complications* / Q000235:genetics*; D018754:Ventricular Dysfunction / Q000209:etiology* / Q000503:physiopathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008070:Lipopolysaccharides; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D008840:Microfilament Proteins; D016601:RNA-Binding Proteins; C000607590:Sorbs2 protein, mouse
keywords: Cardiac dysfunction; LPS; SORBS2; Sepsis; miR-21-3p (miR-21*)