Pharmaceutical Manipulation of Mitochondrial F0F1-ATP Synthase Enables Imaging and Protection of Myocardial Ischemia/Reperfusion Injury Through Stress-induced Selective Enrichment

作者全名："Chen, Zelin; Tan, Xu; Jin, Taotao; Wang, Yu; Dai, Linyong; Shen, Gufang; Zhang, Can; Qu, Langfan; Long, Lei; Shen, Chongxing; Cao, Xiaohui; Wang, Jianwu; Li, Huijuan; Yue, Xiaofeng; Shi, Chunmeng"

作者地址："[Chen, Zelin; Tan, Xu; Jin, Taotao; Wang, Yu; Shen, Gufang; Zhang, Can; Qu, Langfan; Long, Lei; Cao, Xiaohui; Li, Huijuan; Shi, Chunmeng] Army Med Univ, Inst Rocket Force Med, State Key Lab Trauma & Chem Poisoning, Chongqing 400038, Peoples R China; [Dai, Linyong; Shen, Chongxing; Wang, Jianwu; Yue, Xiaofeng] Chongqing Med Univ, Affiliated Hosp 3, Dept Urol, Chongqing 401120, Peoples R China"

通信作者："Shi, CM (通讯作者)，Army Med Univ, Inst Rocket Force Med, State Key Lab Trauma & Chem Poisoning, Chongqing 400038, Peoples R China."

来源：ADVANCED SCIENCE

ESI学科分类：PHYSICS

WOS号：WOS:001125745900001

JCR分区：Q1

影响因子：14.3

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：imaging; ischemia; mitochondria; protection; reperfusion

摘要："To rescue ischemic myocardium from progressing to myocardial infarction, timely identification of the infarct size and reperfusion is crucial. However, fast and accurate identification, as well as the targeted protection of injured cardiomyocytes following ischemia/reperfusion (I/R) injury, remain significantly challenging. Here, a near infrared heptamethine dye IR-780 is shown that has the potential to quickly monitor the area at risk following I/R injury by selectively entering the cardiomyocytes of the at-risk heart tissues. Preconditioning with IR-780 or timely IR-780 administration before reperfusion significantly protects the heart from ischemia and oxidative stress-induced cell death, myocardial remodeling, and heart failure in both rat and pig models. Furthermore, IR-780 can directly bind to F0F1-ATP synthase of cardiomyocytes, rapidly decrease the mitochondrial membrane potential, and subsequently slow down the mitochondrial energy metabolism, which induces the mitochondria into a ""quiescent state"" and results in mitochondrial permeability transition pore inhibition by preventing mitochondrial calcium overload. Collectively, the findings show the feasibility of IR-780-based imaging and protection strategy for I/R injury in a preclinical context and indicate that moderate mitochondrial function depression is a mode of action that can be targeted in the development of cardioprotective reagents. This work identifies a near infrared heptamethine dye, IR-780, exhibiting stress-induced selective enrichment in the at-risk heart tissues following ischemia/reperfusion (I/R) injury and further protecting heart from I/R and oxidative stress induced cell death by targeting the mitochondrial F0F1-ATP synthase of the cardiomyocytes, which promises IR-780 as a potential ischemia-selective agent for imaging and protection of myocardial I/R injury.image"

基金机构："National Natural Science Foundation of China; Shanghai Applied Protein Technology Co., Ltd; Major Program of the National Natural Science Foundation of China [82192884]; Outstanding Scientist Program of Chongqing Talent Plan [CQYC20200101159]; [82072190]"

基金资助正文："The authors thank Professor Ping Wang for NIR image System supporting, thank Professor Chungang Liu for supporting PLA assay, thank Doctor Yinan Deng for pig experiments, thank Shanghai Applied Protein Technology Co., Ltd for supporting non-targeted metabolomics. This work was supported by: Major Program of the National Natural Science Foundation of China (Grant no. 82192884); the National Natural Science Foundation of China (Grant no. 82072190); the Outstanding Scientist Program of Chongqing Talent Plan (CQYC20200101159)."