Inhibition of pyruvate dehydrogenase kinase 4 attenuates myocardial and mitochondrial injury in sepsis-induced cardiomyopathy
Tangtian Chen, Liang Ye, Jing Zhu, Bin Tan, Qin Yi, Yanting Sun, Qiumin Xie, Han Xiang, Rui Wang, Jie Tian, Hao Xu- Infectious Diseases
- Immunology and Allergy
Abstract
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 (PDH) with multifaceted actions in mitochondrial metabolism. However, its role in SIC remains unknown.
Methods
Serum PDK4 levels were measured and analyzed in 27 SIC children, 30 septic children, and 29 healthy children. In addition, the effects of PDK4 knockdown or inhibition on the function and structure of the myocardium and mitochondria of mice exhibiting SIC 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. SIC 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 pyruvate dehydrogenase complex E1 subunit alpha (PDHE1α), improved abnormal pyruvate metabolism and mitochondrial dysfunction.
Conclusions
PDK4 is a potential biomarker for the diagnosis and prognosis of SIC. In experimental SIC, PDK4 promotes mitochondrial dysfunction with increased phosphorylation of PDHE1α and abnormal pyruvate metabolism.