Abstract 14713: MicroRNA-155 Upregulation Mediates Sepsis-Associated Cardiovascular Dysfunction
Background: Sepsis-associated cardiovascular dysfunction remains a leading cause of death in critically ill patients. MicroRNA-155 (miR-155) targets important transcripts in inflammation and cardiovascular system. The present study analyzed the role of miR-155 in experimental and human septic shock.
Methods: Protocol A: Experimental sepsis was induced using endotoxin injection (LPS; 40mg/Kg, ip) or cecal ligation and puncture (CLP) in C57BL/6 (WT; n=40) and miR-155-/- (KO; n=40) male mice. Sepsis-induced cardiovascular dysfunction was evaluated through echocardiography, aortic reactivity to angiotensin II (AngII) and vascular permeability assay; mortality analysis was also performed. Quantification of miR-155, TNF-a, IL-6, IL-1b, AngII receptor 1 (AT1) isoforms (real-time RT- PCR) and NF-kB activation (EMSA) were assessed. Protocol B: Plasma miR-155 concentration was evaluated in septic shock patients on intensive care unit (ICU) admission and compared with healthy controls. Protocol C: Vascular response to AngII and miR-155 expression were analyzed in internal mammary arteries (IMA) from CABG patients after incubation with LPS or vehicle.
Results: MiR-155 levels were increased in plasma, myocardium and aorta in experimental sepsis. This was accompanied by decreased ejection fraction (EF) and cardiac output (CO), aortic hyporreactivity to AngII and increased vascular permeability. In KO, sepsis was associated with higher EF and CO, increased aortic reactivity to AngII and preserved vascular permeability, compared with WT; this was accompanied by ~50% mortality reduction. Experimental sepsis induced pro-inflammatory cytokine upregulation, decreased AT1B expression and NF-kB activation, all of which were attenuated in KO. In human septic shock, miR-155 plasma levels were also increased. In human IMAs, LPS incubation induced miR-155 upregulation and AngII hyporreactivity.
Conclusions: Mir-155 is upregulated in experimental and human septic shock. Mice lacking miR-155 present an attenuation of sepsis-induced cardiovascular dysfunction, blunted proinflammatory activation and AT1 downregulation, as well as reduced mortality. This suggests miR-155 as a potential target in sepsis-associated cardiovascular dysfunction.
- © 2012 by American Heart Association, Inc.