Oxidative-Damaged Mitochondria Activate GABARAPL1-Induced NLRP3 Inflammasomes in an Autophagic-Exosome Manner after Acute Myocardial Ischemia

作者全名："Zhang, Tiechun; Hou, Dongyao; He, Jianrong; Zeng, Xue; Liu, Ruixue; Liu, Liangming; Li, Tao; Xiao, Yingbin; Ma, Ruiyan; Huang, He; Duan, Chenyang"

作者地址："[Zhang, Tiechun; Hou, Dongyao; He, Jianrong; Zeng, Xue; Liu, Ruixue; Huang, He; Duan, Chenyang] Chongqing Med Univ, Dept Anesthesiol, Affiliated Hosp 2, Chongqing 400010, Peoples R China; [Zhang, Tiechun] Chinese Acad Sci, Fifth Peoples Hosp Chongqing, Dept Rehabil, Chongqing 400062, Peoples R China; [Liu, Liangming; Li, Tao] Army Med Univ, Daping Hosp, Dept Shock & Transfus, State Key Lab Trauma Burns & Combined Injury, Chongqing 400042, Peoples R China; [Xiao, Yingbin; Ma, Ruiyan] Army Med Univ, Xinqiao Hosp, Dept Cardiovasc Surg, Chongqing 400037, Peoples R China"

通信作者："Huang, H; Duan, CY (通讯作者)，Chongqing Med Univ, Dept Anesthesiol, Affiliated Hosp 2, Chongqing 400010, Peoples R China.; Ma, RY (通讯作者)，Army Med Univ, Xinqiao Hosp, Dept Cardiovasc Surg, Chongqing 400037, Peoples R China."

来源：OXIDATIVE MEDICINE AND CELLULAR LONGEVITY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000868631300006

JCR分区：Q2

影响因子：7.31

年份：2022

卷号：2022

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Objective. This study is aimed at identifying the potential diagnostic markers for circulating endothelial cells (CECs) for acute myocardial ischemia (AMI) and exploring the regulatory mechanisms of the selected biomarker in mitochondrial oxidative damage and vascular inflammation in AMI pathology. Methods. Utilizing the Gene Expression Omnibus dataset GSE66360, we scanned for differentially expressed genes (DEGs) in 49 AMI patients and 50 healthy subjects. To discover possible biomarkers, LASSO regression and support vector machine recursive feature elimination examinations were conducted. Using the GSE60993 and GSE123342 datasets and AMI rat models, the expression levels and diagnostic accuracy of the biomarkers in AMI were thoroughly verified. CIBERSORT was employed to evaluate the compositional patterns of 22 distinct immunological cell percentages in AMI according to combined cohorts. The oxidative-damaged mitochondria were detected by confocal microscopy observation of MitoTracker, ROS-DCFH-DA, and mCherry-GFP-LC3B. Results. In total, 122 genes were identified. The identified DEGs primarily contributed in arteriosclerosis, arteriosclerotic cardiovascular disorders, bacterial infectious disorder, coronary artery disease, and myocardial infarction. Nine features (NR4A2, GABARAPL1 (GEC1), CLEC4D, ITLN1, SNORD89, ZFP36, CH25H, CCR2, and EFEMP1) of the DEGs were shared by two algorithms, and GABARAPL1 (GEC1) was identified and verified as a diagnostic mitochondrial biomarker for AMI. Confocal results showed that there existed mitochondrial damage and oxidative stress in cardiac CMECs after AMI, and the blocked autophagy flux could be released by exosome burst in cardiac CMECs and blood CECs. Immune cell infiltration testing declared that elevated GEC1 expression in blood CECs was linked to the rise of monocytes and neutrophils. Functional tests revealed that high GEC1 expression in CMECs and CECs could activate the vascular inflammatory response by stimulating NLRP3 inflammasome production after AMI. Conclusion. Oxidative-damaged mitochondria in cardiac CMECs activate GEC1-mediated autophagosomes but block autophagy flux after AMI. The exfoliated cardiac CMECs evolve into abnormal blood CECs, and the undegraded GEC1 autophagosomes produce a large number of NLRP3 inflammasomes by exosome burst, stimulating the increase in monocytes and neutrophils and ultimately triggering vascular inflammation after AMI. Therefore, GEC1 in blood CECs is a highly specific diagnostic mitochondrial biomarker for AMI."

基金机构：National Natural Science Foundation of China; Chongqing Talents Program; Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University; [82272252]; [82270378]; [cstc2022ycjh-bgzxm0007]

基金资助正文："AcknowledgmentsThis work was supported by the National Natural Science Foundation of China (No. 82272252 and 82270378), Chongqing Talents Program (cstc2022ycjh-bgzxm0007), and Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University."