Abstract
Aims:
Nucleotide-binding oligomerization domain-Like Receptor with a Pyrin domain 3 (NLRP3) is considered necessary for initiating a profound sterile inflammatory response. NLRP3 forms multi-protein complexes with Apoptosis-associated Speck-like protein containing a Caspase recruitment domain (ASC) and Caspase-1, which activate pro-interleukin-1β (IL-1β) and pro-IL-18. The role of NLRP3 in cardiac cells is not known. Thus, we investigated the expression and function of NLRP3 during myocardial ischaemia.
Methods and results:
Myocardial infarction (MI) was induced in adult C57BL/6 mice and Wistar rats by ligation of the coronary artery. A marked increase in NLRP3, IL-1β, and IL-18 mRNA expression was found in the left ventricle after MI, primarily located to myocardial fibroblasts. In vitro studies in cells from adult mice showed that myocardial fibroblasts released IL-1β and IL-18 when primed with lipopolysaccharide and subsequently exposed to the danger signal adenosine triphosphate, a molecule released after tissue damage during MI. When hearts were isolated from NLRP3-deficient mice, perfused and subjected to global ischaemia and reperfusion, a marked improvement of cardiac function and reduction of hypoxic damage was found compared with wild-type hearts. This was not observed in ASC-deficient hearts, potentially reflecting a protective role of other ASC-dependent inflammasomes or inflammasome-independent effects of NLRP3.
Conclusion:
This study shows that the NLRP3 inflammasome is up-regulated in myocardial fibroblasts post-MI, and may be a significant contributor to infarct size development during ischaemia-reperfusion.
Keywords:
Heart; IL-1β; Inflammasome; Ischaemia–reperfusion; Myocardial infarction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Animals
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Apoptosis
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Caspase 1 / metabolism
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Cells, Cultured
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Cytoskeletal Proteins / deficiency
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Cytoskeletal Proteins / genetics
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Disease Models, Animal
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Fibroblasts / drug effects
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Fibroblasts / immunology
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Fibroblasts / metabolism*
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Heart Ventricles / drug effects
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Heart Ventricles / immunology
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Heart Ventricles / metabolism*
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Heart Ventricles / pathology
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Heart Ventricles / physiopathology
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Inflammasomes / genetics
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Inflammasomes / metabolism*
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Interleukin-18 / genetics
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Interleukin-18 / metabolism
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism
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Lipopolysaccharides / pharmacology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myocardial Contraction
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Myocardial Infarction / genetics
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Myocardial Infarction / immunology
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Myocardial Infarction / metabolism*
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Myocardial Infarction / pathology
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Myocardial Infarction / physiopathology
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Myocardial Reperfusion Injury / genetics
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Myocardial Reperfusion Injury / immunology
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Myocardial Reperfusion Injury / metabolism*
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Myocardial Reperfusion Injury / pathology
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Myocardial Reperfusion Injury / physiopathology
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Myocardial Reperfusion Injury / prevention & control
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NF-kappa B / metabolism
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NLR Family, Pyrin Domain-Containing 3 Protein
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Potassium / metabolism
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RNA, Messenger / metabolism
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Rats
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Rats, Wistar
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Time Factors
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Toll-Like Receptors / metabolism
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Up-Regulation
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Ventricular Function, Left
Substances
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Carrier Proteins
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Cytoskeletal Proteins
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Inflammasomes
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Interleukin-18
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Interleukin-1beta
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Lipopolysaccharides
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NF-kappa B
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Nlrp3 protein, rat
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Pycard protein, mouse
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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Toll-Like Receptors
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Adenosine Triphosphate
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Caspase 1
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Potassium