Inhibition of Pyruvate Dehydrogenase Kinase 4 Protects Cardiomyocytes from lipopolysaccharide-Induced Mitochondrial Damage by Reducing Lactate Accumulation

作者全名："Chen, Tangtian; Xie, Qiumin; Tan, Bin; Yi, Qin; Xiang, Han; Wang, Rui; Zhou, Qin; He, Bolin; Tian, Jie; Zhu, Jing; Xu, Hao"

作者地址："[Chen, Tangtian; Xie, Qiumin; Tan, Bin; Yi, Qin; Xiang, Han; Wang, Rui; Zhou, Qin; He, Bolin; Tian, Jie; Zhu, Jing; Xu, Hao] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Chongqing Engn Res Ctr Stem Cell Therapy, Minist Educ,Key Lab Child Dev & Disorders,Children, Chongqing 400014, Peoples R China; [Chen, Tangtian] Univ Elect Sci & Technol China, Sichuan Canc Hosp & Inst, Sichuan Canc Ctr, Dept Clin Lab,Sichuan Clin Res Ctr Canc,Affiliated, Chengdu, Peoples R China; [Tian, Jie] Chongqing Med Univ, Dept Cardiovasc Internal Med, Childrens Hosp, Chongqing 400014, Peoples R China; [Xu, Hao] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders,Dept Clin, Chongqing Engn Res Ctr Stem Cell Therapy,Childrens, Minist Educ,Key Lab Child Dev & Disorders,Ctr Clin, 136 Zhongshan 2nd Rd, Chongqing 400014, Peoples R China"

通信作者："Zhu, J; Xu, H (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Chongqing Engn Res Ctr Stem Cell Therapy, Minist Educ,Key Lab Child Dev & Disorders,Children, Chongqing 400014, Peoples R China."

来源：INFLAMMATION

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001167954000003

JCR分区：Q2

影响因子：5.1

年份：2024

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：sepsis-induced cardiomyopathy; PDK4; lactate; mitochondrial dysfunction

摘要："Mitochondrial dysfunction is considered one of the major pathogenic mechanisms of sepsis-induced cardiomyopathy (SIC). Pyruvate dehydrogenase kinase 4 (PDK4), a key regulator of mitochondrial metabolism, is essential for maintaining mitochondrial function. However, its specific role in SIC remains unclear. To investigate this, we established an in vitro model of septic cardiomyopathy using lipopolysaccharide (LPS)-induced H9C2 cardiomyocytes. Our study revealed a significant increase in PDK4 expression in LPS-treated H9C2 cardiomyocytes. Inhibiting PDK4 with dichloroacetic acid (DCA) improved cell survival, reduced intracellular lipid accumulation and calcium overload, and restored mitochondrial structure and respiratory capacity while decreasing lactate accumulation. Similarly, Oxamate, a lactate dehydrogenase inhibitor, exhibited similar effects to DCA in LPS-treated H9C2 cardiomyocytes. To further validate whether PDK4 causes cardiomyocyte and mitochondrial damage in SIC by promoting lactate production, we upregulated PDK4 expression using PDK4-overexpressing lentivirus in H9C2 cardiomyocytes. This resulted in elevated lactate levels, impaired mitochondrial structure, and reduced mitochondrial respiratory capacity. However, inhibiting lactate production reversed the mitochondrial dysfunction caused by PDK4 upregulation. In conclusion, our study highlights the pathogenic role of PDK4 in LPS-induced cardiomyocyte and mitochondrial damage by promoting lactate production. Therefore, targeting PDK4 and its downstream product lactate may serve as promising therapeutic approaches for treating SIC."

基金机构：Science and Technology Research Program of Chongqing Municipal Education Commission

基金资助正文：No Statement Available