Aims

Pyruvate dehydrogenase kinase (PDK) negatively regulates mitochondrial glucose oxidation by inhibiting pyruvate dehydrogenase (PDH). This study aimed to investigate whether targeting this metabolic pathway via PDK inhibition can mitigate hypoxic injury and improve cardiac recovery following myocardial infarction (MI).

Methods

In vivo, a murine model of MI was utilized to evaluate PDK expression and assess the effects of oral PDK inhibitors on cardiac remodeling. In vitro, H9c2 cardiomyoblasts subjected to CoCl₂-induced hypoxia were treated with PDK inhibitors or engineered to express constitutively active PDH to evaluate cell viability, mitochondrial respiration, and reactive oxygen species (ROS) production.

Results

In the murine MI model, PDK expression was significantly elevated in the infarcted myocardium, accompanied by reduced PDH activity. In vitro, pharmacological inhibition of PDK alleviated CoCl₂-induced hypoxic injury, enhanced mitochondrial respiration, and reduced ROS production in H9c2 cells. Furthermore, cells expressing constitutively active PDH exhibited increased resistance to hypoxia-induced apoptosis compared to wild-type cells, underscoring the protective role of sustained PDH activity. In vivo, oral administration of PDK inhibitors significantly improved left ventricular systolic function and attenuated adverse cardiac remodeling at 4 weeks post-MI.

Conclusions

The major outcome of the study is that inhibiting pyruvate dehydrogenase kinase effectively restores mitochondrial metabolism, reduces oxidative stress, and improves left ventricular function, highlighting this metabolic axis as a promising therapeutic target for treating ischemic heart disease.