MiR-21-3P Controls Sepsis-associated Cardiac Dysfunction Via Regulating SORBS2

Objective: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.Methods:E.coli lipopolysaccharide (LPS) (5mg/kg) was administered to C57BL/6 mice to induce a sepsis-induced cardiac dysfunction model within 5-7 h. Cardiac function was assessed by Echocardiography 5-6h post-LPS administration. Myocardium were obtain within 7-9h after LPS treatment for gene expression and protein analysis. A systematic analysis of cardiac miRNA profiles using an established miRNAarray was performed to assess dys-regulated miRNAs in sepsis-induced cardiac dysfunction. Transmission electron microscopy analysis was undertaken of myocardium tissue. To forced expression of miR-21*, miR-21* agomirs were injected in the tail vein of C57BL/6 mice on 3 consecutive days with a total of 30nmol/kg agomir followed by LPS administration.Results: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 dysfunctions 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.Conclusions: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.