Inhibition of Pyruvate Dehydrogenase Kinase 4 Attenuates Myocardial and Mitochondrial Injury in Sepsis-Induced Cardiomyopathy

作者全名："Chen, Tangtian; Ye, Liang; Zhu, Jing; Tan, Bin; Yi, Qin; Sun, Yanting; Xie, Qiumin; Xiang, Han; Wang, Rui; Tian, Jie; Xu, Hao"

作者地址："[Chen, Tangtian; Ye, Liang; Zhu, Jing; Tan, Bin; Yi, Qin; Sun, Yanting; Xie, Qiumin; Xiang, Han; Wang, Rui; Tian, Jie; Xu, Hao] Chongqing Med Univ, Dept Pediat Res Inst, Natl Clin Res Ctr Child Hlth & Disorders,Chongqing, Key Lab Child Dev & Disorders,Minist Educ,Children, Chongqing 400014, Peoples R China; [Ye, Liang] Chongqing Med Univ, Dept Pediat, Women & Childrens Hosp, Chongqing 401147, Peoples R China; [Ye, Liang] Chongqing Hlth Ctr Women & Children, Dept Pediat, Chongqing 401147, Peoples R China; [Sun, Yanting] Soochow Univ, Ctr Clin Lab, Affiliated Hosp 1, Suzhou 215006, Peoples R China; [Tian, Jie] Chongqing Med Univ, Dept Cardiovasc Internal Med, Childrens Hosp, Chongqing 400014, Peoples R China; [Xu, Hao] Chongqing Med Univ, Dept Clin Lab, Childrens Hosp, Chongqing 400014, Peoples R China; [Xu, Hao] Chongqing Med Univ, Childrens Hosp, Dept Clin Lab, Chongqing 400014, Peoples R China"

通信作者："Xu, H (通讯作者)，Chongqing Med Univ, Childrens Hosp, Dept Clin Lab, Chongqing 400014, Peoples R China."

来源：JOURNAL OF INFECTIOUS DISEASES

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001064123000001

JCR分区：Q1

影响因子：5

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：mitochondrial dysfunction; PDHE1 & alpha;; PDK4; pyruvate metabolism; sepsis-induced cardiomyopathy

摘要："Background Sepsis-induced cardiomyopathy (SIC) is a cardiac dysfunction caused by sepsis, with mitochondrial dysfunction being a critical contributor. Pyruvate dehydrogenase kinase 4 (PDK4) is a kinase of pyruvate dehydrogenase with multifaceted actions in mitochondrial metabolism. However, its role in SIC remains unknown.Methods Serum PDK4 levels were measured and analyzed in 27 children with SIC, 30 children with sepsis, and 29 healthy children. In addition, for mice exhibiting SIC, the effects of PDK4 knockdown or inhibition on the function and structure of the myocardium and mitochondria were assessed.Results The findings from the analysis of children with SIC revealed that PDK4 was significantly elevated and correlated with disease severity and organ injury. Nonsurvivors displayed higher serum PDK4 levels than survivors. Furthermore, mice with SIC benefited from PDK4 knockdown or inhibition, showing improved myocardial contractile function, reduced myocardial injury, and decreased mitochondrial structural injury and dysfunction. In addition, inhibition of PDK4 decreased the inhibitory phosphorylation of PDHE1a (pyruvate dehydrogenase complex E1 subunit a) and improved abnormal pyruvate metabolism and mitochondrial dysfunction.Conclusions PDK4 is a potential biomarker for the diagnosis and prognosis of SIC. In experimental SIC, PDK4 promoted mitochondrial dysfunction with increased phosphorylation of PDHE1a and abnormal pyruvate metabolism."

基金机构："National Natural Science Foundation of China [81700250, 81670270, 82270271]; Ministry of Education Key Laboratory of Child Development and Disorders [GBRP-202108]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (81700250, 81670270, and 82270271) and the General Basic Research Project from the Ministry of Education Key Laboratory of Child Development and Disorders (GBRP-202108)."