title: TXNIP mediates NLRP3 inflammasome activation in cardiac microvascular endothelial cells as a novel mechanism in myocardial ischemia/reperfusion injury.
abstract: NLRP3 inflammasome is necessary for initiating acute sterile inflammation. Recent studies have demonstrated that NLRP3 inflammasome is up-regulated and mediates myocardial ischemia/reperfusion (MI/R) injury. However, the signaling pathways that lead to the activation of NLRP3 inflammasome by MI/R injury have not been fully elucidated. C57BL/6J mice were subjected to 30 min ischemia and 3 or 24 h reperfusion. The ischemic heart exhibited enhanced inflammasome activation as evidenced by increased NLRP3 expression and caspase-1 activity and increased IL-1β and IL-18 production. Intramyocardial NLRP3 siRNA injection or an intraperitoneal injection of BAY 11-7028, an inflammasome inhibitor, attenuated macrophage and neutrophil infiltration and decreased MI/R injury, as measured by cardiomyocyte apoptosis and infarct size. The ischemic heart also exhibited enhanced interaction between Txnip and NLRP3, which has been shown to be a mechanism for activating NLRP3. Intramyocardial Txnip siRNA injection also decreased infarct size and NLRP3 activation. In vitro experiments revealed that NLRP3 was expressed in cardiac microvascular endothelial cells (CMECs), but was hardly expressed in cardiomyocytes. Simulated ischemia/reperfusion (SI/R) stimulated NLRP3 inflammasome activation in CMECs, but not in cardiomyocytes. Moreover, CMECs subjected to SI/R injury increased interactions between Txnip and NLRP3. Txnip siRNA diminished NLRP3 inflammasome activation and SI/R-induced injury, as measured by LDH release and caspase-3 activity in CMECs. ROS scavenger dissociated TXNIP from NLRP3 and inhibited the activation of NLRP3 inflammasome in the CMECs. For the first time, we demonstrated that TXNIP-mediated NLRP3 inflammasome activation in CMECs was a novel mechanism of MI/R injury. Interventions that block Txnip/NLRP3 signaling to inhibit the activation of NLRP3 inflammasomes may be novel therapies for mitigating MI/R injury.
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, 15 Changle West Road, Xi'an, 710032, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Kun
authors.initials: K
authors.lastname: Lian
authors.forename: Lijian
authors.initials: L
authors.lastname: Zhang
authors.forename: Rutao
authors.initials: R
authors.lastname: Wang
authors.forename: Fu
authors.initials: F
authors.lastname: Yi
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.forename: Chao
authors.initials: C
authors.lastname: Xin
authors.forename: Di
authors.initials: D
authors.lastname: Zhu
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Wenjun
authors.initials: W
authors.lastname: Yan
authors.forename: Lize
authors.initials: L
authors.lastname: Xiong
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Haichang
authors.initials: H
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Tao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D006321:Heart / Q000503:physiopathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D058847:Inflammasomes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D060888:Real-Time Polymerase Chain Reaction; D013879:Thioredoxins / Q000378:metabolism*; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C445672:Txnip protein, mouse; D013879:Thioredoxins