The Study Of The Mechanical Role Of Nlrp3Inflammasome In Ischemic Diseases

Aim：Ischemic diseases, including coronary heart disease and peripheral vascular embolicdisease, seriously affect public health. Nlrp3inflammasome is a newly identified molecularthat could modulate the secretion of interleukin-1β(IL-1β) and interleukin-18(IL-18),which governs the inflammatory response. The purpose of this study is to illustrate thepossible role of Nlrp3inflammasome in ischemic diseases, by testing the local Nlrp3expression in clinical patients. And then explore the role of Nlrp3inflammasomes in therecovery/reperfusion of ischemic disease, using genetic knockdown models. Finally we try tofind the novel ways that could activate Nlrp3inflammasome in cell level.Methods and results: We compared the expression of Nlrp3inflammasome in epicardialadipose tissue and peripheral blood mononuclear cells（PBMCs）from the patient in cardiacsurgery unit. The patients suffering from CABG are viewed as coronary artery diseasepatients (CAD) and the patients suffering from valvular replacement surgery orcongenitalheart diseases (coronary artery disease was excluded) are viewed as non-coronary arterydisease patients (NCAD). The expression level of Nlrp3inflammasome was significantlyincreased in the epicardial tissue and PBMCs of the CAD patients. We then observed thatknockdown of the key component of Nlrp3inflammasome could worsen the recovery rate ofhindlimb ischemia in mouse. The ability of mobilization and adhesion of EPCs weredampened in the knockout mice compared with the wild type mice. While the ability ofmigration and tube formation was not affected. The mitochondrial derived DAMP fMLPcould induce the secretion of IL-1βfrom bone marrow derived macrophages （BMMMCs）after LPS pretreatment. Furthermore, only hypoxia could not activate Nlrp3inflammasome.However, the combined effect of hypoxia and LPS or hypoxia and fMLP could activate Nlrp3inflammasome.Conclusion: Our study illustrated the role of Nlrp3inflammasome in ischemia diseases. TheNlrp3inflammasome were relevant to coronary artery disease, and it promoted angiogenesisin vivo. The mitochondrial derived DAMP fMLP could activate Nlrp3inflammasome, whichcan be served as a potential therapeutic target in future.