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

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Abstract

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.

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Funding

This work was supported by the Chongqing Science and Technology Bureau (No. CSTB2023NSCQ-MSX0603), China Postdoctoral Science Foundation (No. 2023M730447), the National Natural Science Foundation of China grants (No. 82270271), and the Science and Technology Research Program of Chongqing Municipal Education Commission (No. KJQN202300421).

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  1. Tangtian Chen and Qiumin Xie have contributed equally.

Authors and Affiliations

  1. Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Engineering Research Center of Stem Cell Therapy, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China

    Tangtian Chen, Qiumin Xie, Bin Tan, Qin Yi, Han Xiang, Rui Wang, Qin Zhou, Bolin He, Jie Tian, Jing Zhu & Hao Xu

  2. Department of Clinical Laboratory, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China

    Tangtian Chen

  3. Department of Cardiovascular (Internal Medicine), Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China

    Jie Tian

  4. Department of Clinical Laboratory, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Engineering Research Center of Stem Cell Therapy, Children’s Hospital of Chongqing Medical University, Box 136, No. 3 Zhongshan RD, Yuzhong District, Chongqing, 400014, China

    Hao Xu

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Contributions

T.T.C., Q.M.X., J.Z., and H.X. (Hao Xu) designed experiments. T.T.C. drafted the manuscript. T.T.C., Q.M.X., B.T., Q.Y., J.Z., and H.X. (Hao Xu) edited the manuscript. T.T.C., Q.M.X., H.X. (Han Xiang), R.W., Q.Z., and B.L.H. performed the experiments in vitro. T.T.C., Q.M.X., J.Z., and H.X. (Hao Xu) take responsibility for the accuracy of the analysis of the whole experiment.

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Correspondence to Jing Zhu or Hao Xu.

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Chen, T., Xie, Q., Tan, B. et al. Inhibition of Pyruvate Dehydrogenase Kinase 4 Protects Cardiomyocytes from lipopolysaccharide-Induced Mitochondrial Damage by Reducing Lactate Accumulation. Inflammation (2024). https://doi.org/10.1007/s10753-024-01981-z

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