title: Necrostatin-1 inhibits Hmgb1-IL-23/IL-17 pathway and attenuates cardiac ischemia reperfusion injury.
abstract: Ischemia reperfusion (IR) injury is a major issue in cardiac transplantation and inflammatory processes play a major role in myocardial IR injury. Necrostatin-1 (Nec-1) is a small molecule capable of inhibiting RIP1 kinase activity and attenuates inflammation-mediated tissue injury. In our study, hearts of C57Bl/6 mice were flushed and stored in cold Bretschneider solution for 8 h and then transplanted into syngeneic recipients. We found that Nec-1 decreased cardiomyocyte necrosis and recruitment of neutrophils and macrophages. Troponin T (TnT) production on 24 h after myocardial IR injury was reduced by Nec-1 administration. Cardiac output at 60 mmHg of afterload pressure was significantly increased in hearts with Nec-1 administration and the cardiac allograft survival in Nec-1-treated animals was significantly prolonged (MST = 90 days in IR + Nec-1 group, P < 0.05 as compared with IR group, MST = 83.5 days). Nec-1 treatment attenuated ROS generation and increased expression of NOS2 and COX-2. The expression of Hmgb1, IL-23, and IL-17A were also decreased with Nec-1 administration. Furthermore, the decreased TnT expression induced by Nec-1 was abrogated with exogenous Hmgb1 administration. In conclusion, Nec-1 played a protective role in cardiomyocyte IR injury, and this was associated with inhibited Hmgb1-IL-23/IL-17 pathway.
authors.affiliation: Department of Rheumatology and Immunology, Xiangyang Central Hospital, Hubei University of Arts and Science, Hubei, China.
authors.forename: Anbin
authors.initials: A
authors.lastname: Zhang
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Mao
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Yunjie
authors.initials: Y
authors.lastname: Tong
authors.forename: Yanli
authors.initials: Y
authors.lastname: Huang
authors.forename: Yanli
authors.initials: Y
authors.lastname: Lan
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000517:prevention & control; D024243:HMGB1 Protein / Q000276:immunology / Q000378:metabolism; D016027:Heart Transplantation / Q000009:adverse effects* / Q000379:methods; D007093:Imidazoles / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000494:pharmacology*; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D053759:Interleukin-23 / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects*; D016042:Transplantation, Heterotopic; D020107:Troponin T / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; D007093:Imidazoles; D007211:Indoles; D020381:Interleukin-17; D053759:Interleukin-23; D017382:Reactive Oxygen Species; D020107:Troponin T; C507699:necrostatin-1
keywords: Hmgb1; interleukin-23/interleukin-17; ischemia reperfusion injury; necrostatin-1