Loss of duplexmiR-223 (5p and 3p) aggravates myocardial depression and mortality in polymicrobial sepsis.
Sepsis is the leading cause of death in critically ill patients. While myocardial dysfunction has been recognized as a major manifestation in severe sepsis, the underlying molecular mechanisms associated with septic cardiomyopathy remain unclear. In this study, we performed a miRNA array analysis in hearts collected from a severe septic mouse model induced by cecal ligation and puncture (CLP). Among the 19 miRNAs that were dys-regulated in CLP-mouse hearts, miR-223(3p) and miR-223*(5p) were most significantly downregulated, compared with sham-operated mouse hearts. To test whether a drop of miR-223 duplex plays any roles in sepsis-induced cardiac dysfunction and inflammation, a knockout (KO) mouse model with a deletion of the miR-223 gene locus and wild-type (WT) mice were subjected to CLP or sham surgery. We observed that sepsis-induced cardiac dysfunction, inflammatory response and mortality were remarkably aggravated in CLP-treated KO mice, compared with control WTs. Using Western-blotting and luciferase reporter assays, we identified Sema3A, an activator of cytokine storm and a neural chemorepellent for sympathetic axons, as an authentic target of miR-223* in the myocardium. In addition, we validated that miR-223 negatively regulated the expression of STAT-3 and IL-6 in mouse hearts. Furthermore, injection of Sema3A protein into WT mice revealed an exacerbation of sepsis-triggered inflammatory response and myocardial depression, compared with control IgG1 protein-treated WT mice following CLP surgery. Taken together, these data indicate that loss of miR-223/-223* causes an aggravation of sepsis-induced inflammation, myocardial dysfunction and mortality. Our study uncovers a previously unrecognized mechanism underlying septic cardiomyopathy and thereby, may provide a new strategy to treat sepsis.
Department of Pharmacology and Cell Biophysics.
Xiaohong
X
Wang
Department of Pathology and Laboratory Medicine.
Wei
W
Huang
Department of Pharmacology and Cell Biophysics.
Yang
Y
Yang
Department of Pathology and Laboratory Medicine.
Yigang
Y
Wang
Critical Illness Research, Lawson Health Research Institute, Ontario N6A 4G5, Canada.
Tianqing
T
Peng
Institute of Biosciences and Technology, Texas A&M Health Science Center, TX, USA.
Jiang
J
Chang
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Charles C
CC
Caldwell
Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Basilia
B
Zingarelli
Department of Pharmacology and Cell Biophysics. Electronic address: fangg@ucmail.uc.edu.
Guo-Chang
GC
Fan
D000818:Animals; D001483:Base Sequence; D060085:Coinfection / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*; D017931:DNA Primers; D005260:Female; D006321:Heart / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D018805:Sepsis / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*
D017931:DNA Primers; C544877:MIRN223 microRNA, mouse; D035683:MicroRNAs
Inflammation; MicroRNA; Myocardial depression; Sema3A; Sepsis