Necrostatin‐1 inhibits Hmgb1‐IL‐23/IL‐17 pathway and attenuates cardiac ischemia reperfusion injury

• Published in: Transplant international Vol. 27; no. 10; pp. 1077 - 1085
• Main Authors: Zhang, Anbin, Mao, Xiaogang, Li, Lin, Tong, Yunjie, Huang, Yanli, Lan, Yanli, Jiang, Hong
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.10.2014
• Subjects: Animals; Disease Models, Animal; Graft Rejection - prevention & control; Heart Transplantation - adverse effects; Heart Transplantation - methods; Hmgb1; HMGB1 Protein - immunology; HMGB1 Protein - metabolism; Imidazoles - pharmacology; In Situ Nick-End Labeling; Indoles - pharmacology; Interleukin-17 - immunology; Interleukin-17 - metabolism; Interleukin-23 - immunology; Interleukin-23 - metabolism; interleukin‐23/interleukin‐17; ischemia reperfusion injury; Male; Mice; Mice, Inbred C57BL; Muscle Cells; Myocardial Reperfusion Injury - drug therapy; Myocardial Reperfusion Injury - physiopathology; necrostatin‐1; Random Allocation; Reactive Oxygen Species - metabolism; Real-Time Polymerase Chain Reaction; Sensitivity and Specificity; Signal Transduction - drug effects; Transplantation, Heterotopic; Troponin T - metabolism; Hmgb1; ischemia reperfusion injury; interleukin-23/interleukin-17; necrostatin-1
• ISSN: 0934-0874; 1432-2277
• DOI: 10.1111/tri.12349

Summary 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.