
CircTLK1 modulates sepsis‐induced cardiomyocyte apoptosis via enhancing PARP1/HMGB1 axis–mediated mitochondrial DNA damage by sponging miR‐17‐5p
Author(s) -
Qiu Yu,
Yu Ying,
Qin XiaoMei,
Jiang Tao,
Tan YanFang,
Ouyang WenXian,
Xiao ZhengHui,
Li ShuangJie
Publication year - 2021
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.16738
Subject(s) - apoptosis , parp1 , microbiology and biotechnology , hmgb1 , dna damage , mitochondrial dna , cancer research , chemistry , microrna , biology , dna , poly adp ribose polymerase , polymerase , biochemistry , gene , receptor
Septic cardiomyopathy is a common complication of sepsis with high morbidity and mortality, but lacks specific therapy. This study aimed to reveal the role of circTLK1 and its potential mechanisms in septic cardiomyopathy. Materials and Methods The in vitro and in vivo models of septic cardiomyopathy were established. Cell viability and apoptosis were detected by CCK8, TUNEL and flow cytometry, respectively. LDH, CK, SOD, MDA, ATP, 8‐OHdG, NAD+/NADH ratio, ROS level, mitochondrial membrane potential and cytochrome C distribution were evaluated using commercial kits. qRT‐PCR and western blotting were performed to detect RNA and protein levels. Mitochondrial DNA (mtDNA) copy number and transcription were assessed by quantitative PCR. Dual‐luciferase assay, RNA immunoprecipitation and co‐immunoprecipitation were performed to verify the interaction between circTLK1/PARP1 and miR‐17‐5p. Results CircTLK1, PARP1 and HMGB1 were up‐regulated in the in vitro and in vivo models of septic cardiomyopathy. CircTLK1 inhibition restrained LPS‐induced up‐regulation of PARP1 and HMGB1. Moreover, circTLK1 knockdown repressed sepsis‐induced mtDNA oxidative damage, mitochondrial dysfunction and consequent cardiomyocyte apoptosis by inhibiting PARP1/HMGB1 axis in vitro and in vivo. In addition, circTLK1 enhanced PARP1 expression via sponging miR‐17‐5p. Inhibition of miR‐17‐5p abolished the protective effects of circTLK1 silencing on oxidative mtDNA damage and cardiomyocyte apoptosis. Conclusion CircTLK1 sponged miR‐17‐5p to aggravate mtDNA oxidative damage, mitochondrial dysfunction and cardiomyocyte apoptosis via activating PARP1/HMGB1 axis during sepsis, indicating that circTLK1 may be a putative therapeutic target for septic cardiomyopathy.