• Øystein Sandanger, Trine Ranheim, Leif Erik Vinge, Marte Bliksøen, Katrine Alfsnes, Alexandra V Finsen, Christen P Dahl, Erik T Askevold, Geir Florholmen, Geir Christensen, Katherine A Fitzgerald, Egil Lien, Guro Valen, Terje Espevik, Pål Aukrust, and Arne Yndestad.
• Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo N-0027, Norway.
• Cardiovasc. Res. 2013 Jul 1; 99 (1): 164-74.

AimsNucleotide-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 ResultsMyocardial 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.ConclusionThis 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.

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