Carbon monoxide releasing molecule-3 improves myocardial function in mice with sepsis by inhibiting NLRP3 inflammasome activation in cardiac fibroblasts

Basic Res Cardiol. 2017 Mar;112(2):16. doi: 10.1007/s00395-017-0603-8. Epub 2017 Feb 6.


The NLRP3 inflammasome is an intracellular multiple-protein complex that controls the maturation and release of interleukin (IL)-1β and IL-18. Endogenous carbon monoxide (CO) is anti-inflammatory. The aim of this study was to assess the effects/mechanisms of CO-releasing molecule-3 (CORM-3)-dependent modulation of the NLRP3 inflammasome in cardiac fibroblasts (CF) and its effect on myocardial function in sepsis. CF were treated with CORM-3 or inactive CORM-3 (iCORM-3) before NLRP3 inflammasome priming with lipopolysaccharides (LPS) or following activation with adenosine triphosphate (ATP). In parallel, cardiomyocytes (CM) were challenged with supernatants of LPS/ATP-stimulated CF or a cytokine mixture (Cyto-mix) containing IL-1β, IL-18, and HMGB1. In vivo, mice were treated with CORM-3 before or after LPS to induce sepsis (endotoxemia). Pretreatment of CF with CORM-3 prevented an LPS-induced increase in NLRP3 and pro-IL-1β expression. Treatment of CF with CORM-3 before ATP prevented ATP-induced activation of the NLRP3 inflammasome. Challenging CF with LPS/ATP promoted NLRP3 interactions with adaptor ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain), which was prevented by CORM-3. Challenging CM with supernatants of CF with LPS/ATP or Cyto-mix (IL-1β, IL-18, and HMGB1) resulted in CM apoptosis, which was attenuated with either a CORM-3 or IL-1 receptor antagonist. Finally, myocardial NLRP3 inflammasome activation and myocardial dysfunction in septic mice were abolished by CORM-3. In NLRP3-deficient mice with sepsis, CORM-3 did not show additional benefits in improving myocardial function. Our results indicate that CORM-3 suppresses NLRP3 inflammasome activation by blocking NLRP3 interactions with the adaptor protein ASC and attenuates myocardial dysfunction in mice with sepsis.

Keywords: Carbon monoxide; Cardiac fibroblast–cardiomyocyte interaction; Myocardial dysfunction; NLRP3 inflammasome; Sepsis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Blotting, Western
  • Carbon Monoxide / pharmacology
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Fluorescent Antibody Technique
  • Heart / drug effects
  • Immunoprecipitation
  • Inflammasomes / drug effects*
  • Inflammasomes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Myocardium / metabolism
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Organometallic Compounds / metabolism
  • Organometallic Compounds / pharmacology*
  • Sepsis / complications*
  • Sepsis / metabolism


  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Organometallic Compounds
  • tricarbonylchloro(glycinato)ruthenium(II)
  • Carbon Monoxide