Abstract
Myocardial contractile dysfunction in sepsis is associated with the increased morbidity and mortality. Although the underlying mechanisms of the cardiac depression have not been fully elucidated, an exaggerated inflammatory response is believed to be responsible. Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome is an intracellular platform that is involved in the maturation and release of interleukin (IL)-1β. The aim of the present study is to evaluate whether sepsis activates NLRP3 inflammasome/caspase-1/IL-1β pathway in cardiac fibroblasts (CFs) and whether this cytokine can subsequently impact the function of cardiomyocytes (cardiac fibroblast-myocyte cross-talk). We show that treatment of CFs with lipopolysaccharide (LPS) induces upregulation of NLRP3, activation of caspase-1, as well as the maturation (activation) and release of IL-1β. In addition, the genetic (small interfering ribonucleic acid [siRNA]) and pharmacological (glyburide) inhibition of the NLRP3 inflammasome in CFs can block this signaling pathway. Furthermore, the inhibition of the NLRP3 inflammasome in cardiac fibroblasts ameliorated the ability of LPS-chalenged CFs to impact cardiomyocyte function as assessed by intracellular cyclic adenosine monophosphate (cAMP) responses in cardiomyocytes. Salient features of this the NLP3 inflammasome/ caspase-1 pathway were confirmed in in vivo models of endotoxemia/sepsis. We found that inhibition of the NLRP3 inflammasome attenuated myocardial dysfunction in mice with LPS and increased the survival rate in mice with feces-induced peritonitis. Our results indicate that the activation of the NLRP3 inflammasome in cardiac fibroblasts is pivotal in the induction of myocardial dysfunction in sepsis.
Highlights
Sepsis and septic shock are common entities encountered in intensive care units and they are associated with high mortality rates [4,39]
In order to determine whether LPS treatment activates the NLRP3 inflammasome and subsequent processing and secretion of IL-1b in cardiac fibroblasts (CFs), we measured the intracellular levels of NLRP3, pro-caspase-1, caspase-1 p10, proIL-1b, as well as the intracellular and released IL-1b
These results are consistent with the NLRP3 inflammasome/caspase-1 pathway being operative in LPS-challenged cardiac fibroblasts
Summary
Sepsis and septic shock are common entities encountered in intensive care units and they are associated with high mortality rates [4,39]. The heart is one of the organs affected in MOF and myocardial dysfunction is associated with poor outcomes [23]. As the most important functional cells within the heart, most experimental studies addressing the mechanisms of sepsis-induced myocardial dysfunction have focused on the cardiomyocyte. The cross-talk between the CFs and cardiomyocytes can be mediated by paracrine signalling, direct cell–cell contact via micro tubules, and through indirect interactions via the extracellular matrix [46]. These interactions are important in normal cardiac functioning, but they play roles in myocardial pathologies [13,31,46]
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