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J Immunol. 2015 Jul 15;195(2):672-82. doi: 10.4049/jimmunol.1403155. Epub 2015 Jun 5.

Attenuation of Cardiac Dysfunction in Polymicrobial Sepsis by MicroRNA-146a Is Mediated via Targeting of IRAK1 and TRAF6 Expression.

Author information

  • 1Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614;
  • 2Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614; Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614;
  • 3Department of Geriatrics, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China;
  • 4Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614; Department of Biometry and Medical Computing, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614; and.
  • 5Animal Model Research Center, Nanjing University, Nanjing, 210093 China.
  • 6Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614; Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614; Li@etsu.edu.

Abstract

Cardiac dysfunction is a major consequence of sepsis/septic shock and contributes to the high mortality of sepsis. Innate and inflammatory responses mediated by TLRs play a critical role in sepsis-induced cardiac dysfunction. MicroRNA-146 (miR-146) was first identified as a negative regulator in innate immune and inflammatory responses induced by LPS. This study examined whether miR-146a will have a protective effect on sepsis-induced cardiac dysfunction. Lentivirus-expressing miR-146a (LmiR-146a) or lentivirus-expressing scrambled miR (LmiR-control) was delivered into the myocardium via the right carotid artery. Seven days after transfection, mice were subjected to cecal ligation and puncture (CLP). Untransfected mice were also subjected to CLP-induced sepsis. Cardiac function was examined by echocardiography before and 6 h after CLP. In vitro studies showed that increased miR-146a levels suppress LPS-induced IκBα phosphorylation and inflammatory cytokine production in both H9C2 cardiomyocytes and J774 macrophages. In vivo transfection of LmiR-146a attenuated sepsis-induced cardiac dysfunction. The values for percent ejection fraction and percent fractional shortening in LmiR-146a-transfected CLP mice were significantly greater than in untransfected CLP control. LmiR-146a transfection prevented sepsis-induced NF-κB activity, suppressed IRAK and TRAF6 expression in the myocardium, and attenuated sepsis-induced inflammatory cytokine production in both plasma and peritoneal fluid. In addition, LmiR-146a transfection decreased sepsis-induced infiltration of neutrophils and macrophages into the myocardium. LmiR-146a can also transfect macrophages in the periphery. We conclude that miR-146a attenuates sepsis-induced cardiac dysfunction by preventing NF-κB activation, inflammatory cell infiltration, and inflammatory cytokine production via targeting of IRAK and TRAF6 in both cardiomyocytes and inflammatory monocytic cells.

Copyright © 2015 by The American Association of Immunologists, Inc.

PMID:
26048146
[PubMed - indexed for MEDLINE]
PMCID:
PMC4490963
[Available on 2016-07-15]

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