PMID- 32686827 OWN - NLM STAT- MEDLINE DCOM- 20210330 LR - 20210330 IS - 1573-4935 (Electronic) IS - 0144-8463 (Print) IS - 0144-8463 (Linking) VI - 40 IP - 8 DP - 2020 Aug 28 TI - Attenuating ischemia/reperfusion injury in rat cardiac transplantation by intracoronary infusion with siRNA cocktail solution. LID - 10.1042/BSR20193937 [doi] LID - BSR20193937 AB - Tumor necrosis factor-alpha (TNF-alpha), caspase-8, and complement component 5a receptor (C5aR) are known to play a crucial role in the myocardial ischemia/reperfusion (I/R) injury in cardiac transplantation. We hypothesized that the intracoronary infusion of TNF-alpha, caspase-8, and C5aR small interfering RNAs (siRNA) would protect cardiac allograft function and improve graft survival from I/R injury-induced organ failure. I/R injury of cardiac allograft was induced by syngeneic rat cardiac transplantation, in which the transplanted hearts were infused with saline or different amounts of siRNA cocktail solution targeting TNF-alpha, caspase-8, and C5aR via coronary arteries, and subsequently subjected to 18 h of preservation at 4 degrees C in histidine-tryptophan-ketoglutarate (HTK) solution. The effects of siRNA cocktail solution on prolonged cold I/R injury were determined by assessing graft survival, histopathological changes, myeloperoxidase (MPO) activity, and malondialdehyde (MDA) concentration. The perfused siRNA cocktail solution successfully knocked down the expression of TNF-alpha, caspase-8, and C5aR in vitro and in vivo. Approximately 91.7% of control hearts that underwent 18 h of cold ischemia ceased their function after transplantation; however, 87.5% of cardiac allografts from the highest dose siRNA cocktail solution-pretreated hearts survived >14 days and exhibited minimal histological changes, with minimal cellular infiltration, interstitial edema, and inflammation and maximal reduced MPO activity and MDA concentration in the cardiac allograft. We demonstrated the feasibility and efficiency of infusion of TNF-alpha, caspase-8, and C5aR siRNA via the intracoronary route as a promising strategy for gene silencing against I/R injury in cardiac transplantation. CI - (c) 2020 The Author(s). FAU - Yang, Bo AU - Yang B AD - Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China. AD - NHC Key Laboratory of Organ Transplantation, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China. FAU - Wang, Jin AU - Wang J AD - Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China. AD - NHC Key Laboratory of Organ Transplantation, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China. FAU - Zhao, Yuanyuan AU - Zhao Y AD - Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China. AD - NHC Key Laboratory of Organ Transplantation, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China. FAU - Duan, Wu AU - Duan W AD - Division of Endocrinology, Department of Internal Medicine, Qilu Hospital of Shandong University, Jinan, China. AD - Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. FAU - Dai, Chen AU - Dai C AD - Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China. AD - NHC Key Laboratory of Organ Transplantation, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China. FAU - Han, Zhenyi AU - Han Z AD - Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China. AD - NHC Key Laboratory of Organ Transplantation, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China. FAU - Wang, Meixi AU - Wang M AD - Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China. AD - NHC Key Laboratory of Organ Transplantation, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China. FAU - Zhang, Bo AU - Zhang B AD - Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China. AD - NHC Key Laboratory of Organ Transplantation, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China. FAU - Wei, Lai AU - Wei L AD - Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China. AD - NHC Key Laboratory of Organ Transplantation, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China. FAU - Chen, Zhishui AU - Chen Z AD - Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China. AD - NHC Key Laboratory of Organ Transplantation, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China. FAU - Chen, Dong AU - Chen D AD - Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China. AD - NHC Key Laboratory of Organ Transplantation, Wuhan 430030, China. AD - Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Biosci Rep JT - Bioscience reports JID - 8102797 RN - 0 (RNA, Small Interfering) RN - 0 (Receptor, Anaphylatoxin C5a) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 3.4.22.- (Casp8 protein, rat) RN - EC 3.4.22.- (Caspase 8) SB - IM MH - Animals MH - Caspase 8/genetics/*metabolism MH - Coronary Vessels MH - Disease Models, Animal MH - Graft Survival MH - *Heart Transplantation MH - Infusions, Intra-Arterial MH - Male MH - Myocardial Reperfusion Injury/genetics/metabolism/pathology/*prevention & control MH - Myocardium/*metabolism/pathology MH - RNA Interference MH - RNA, Small Interfering/*administration & dosage MH - *RNAi Therapeutics MH - Rats, Inbred Lew MH - Receptor, Anaphylatoxin C5a/genetics/*metabolism MH - Time Factors MH - Tumor Necrosis Factor-alpha/genetics/*metabolism PMC - PMC7403945 OTO - NOTNLM OT - Cardiac transplantation OT - Graft survival OT - Intracoronary infusion OT - Oxidative stress damage OT - Small interfering RNAs COIS- The authors declare that there are no competing interests associated with the manuscript. EDAT- 2020/07/21 06:00 MHDA- 2021/03/31 06:00 PMCR- 2020/08/04 CRDT- 2020/07/21 06:00 PHST- 2019/12/01 00:00 [received] PHST- 2020/07/09 00:00 [revised] PHST- 2020/07/15 00:00 [accepted] PHST- 2020/07/21 06:00 [pubmed] PHST- 2021/03/31 06:00 [medline] PHST- 2020/07/21 06:00 [entrez] PHST- 2020/08/04 00:00 [pmc-release] AID - 225833 [pii] AID - BSR20193937 [pii] AID - 10.1042/BSR20193937 [doi] PST - ppublish SO - Biosci Rep. 2020 Aug 28;40(8):BSR20193937. doi: 10.1042/BSR20193937.