Nicotinamide mononucleotide protects septic hearts in mice via preventing cyclophilin F modification and lysosomal dysfunction  

作　　者：Rui Ni Xiao-yun Ji Ting Cao Xiu-wen Liu Chao Wang Chao Lu Angel Peng Zhu-xu Zhang Guo-Chang Fan Jin Zhang Zhao-liang Su Tian-qing Peng 

机构地区：[1]International Genome Center,Jiangsu University,Zhenjiang,212013,China [2]Department of Pathology and Laboratory Medicine,Western University,London,ON,Canada [3]Lawson Health Research Institute,London Health Sciences Centre,London,ON,Canada [4]Institutes of Biology and Medical Sciences and Institute for Cardiovascular Science,Soochow University,Suzhou,215123,China [5]Affiliated Hospital,Jiangsu University,Zhenjiang,212013,China [6]School of Medicine,Jiangsu University,Zhenjiang,212013,China [7]Department of Chemical and Biochemical Engineering,Western University,London,ON,Canada [8]Department of Medicine,Western University,London,ON,Canada [9]Department of Pharmacology and Systems Physiology,University of Cincinnati College of Medicine,Cincinnati,OH,USA

出　　处：《Acta Pharmacologica Sinica》2025年第4期976-988,共13页中国药理学报(英文版)

基　　金：supported by the Canadian Institute of Health Research(Grant No.PJT-180304 to TQP);Projects of International Cooperation from Jiangsu,China(Grant No.BZ2024031 to ZLS).

摘　　要：Myocardial dysfunction is a decisive factor of death in septic patients.Cyclophilin F(PPIF)is a major component of the mitochondrial permeability transition pore(mPTP)and acts as a critical mPTP sensitizer triggering mPTP opening.In sepsis,decreased NAD+impairs Sirtuin 3 function,which may prevent PPIF de-acetylation.Repletion of NAD^(+)with nicotinamide mononucleotide(NMN)reduces myocardial dysfunction in septic mice.In addition,administration of the mPTP inhibitor cyclosporine-A attenuated sepsis-induced myocardial dysfunction,and deletion of PPIF reduced lung and liver injuries in sepsis,leading to increased survival.It is plausible that NAD+repletion with NMN may prevent mPTP opening in protecting septic hearts through PPIF de-acetylation and/or inhibition of mitochondrial ROS-mediated PPIF oxidation.In this study we investigated how NMN alleviated myocardial dysfunction in septic mice.Sepsis was induced in mice by injection of LPS(4 mg/kg,i.p.).Then mice received NMN(500 mg/kg,i.p.)or mito-TEMPO(0.7 mg/kg,i.p.)right after LPS injection,and subjected to echocardiography for assessing myocardial function.At the end of experiment,the heart tissues and sera were collected for analyses.In vitro experiments were conducted in neonatal mouse cardiomyocytes treated with LPS(1µg/mL)in the presence of NMN(500µmol/L)or mito-TEMPO(25 nmol/L).We showed that LPS treatment markedly increased mitochondrial ROS production and induced lysosomal dysfunction and aberrant autophagy in cardiomyocytes and mouse hearts,leading to inflammatory responses and myocardial injury and dysfunction in septic mice.NMN administration attenuated LPS-induced deteriorative effects.Selective inhibition of mitochondrial superoxide production with mito-TEMPO attenuated lysosomal dysfunction and aberrant autophagy in septic mouse hearts.Notably,LPS treatment significantly increased acetylation and oxidation of PPIF,which was prevented by NMN in mouse hearts.Knockdown of PPIF replicated the beneficial effects of NMN or mito-TEMPO on ROS production,l

关 键 词：SEPSIS cyclophilin F LPS myocardial dysfunction nicotinamide mononucleotide Mito-TEMPO 

分 类 号：R459.7[医药卫生—急诊医学]