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.