The cAMP-PKA signaling pathway induces apoptosis and promotes hypothermic liver injury

BACKGROUND: The mechanisms underlying hypothermic liver injury necessitate investigation for the development of effective diagnostic and therapeutic approaches. We aim to establish a model of hypothermic liver injury to explore the hepatic alterations, thereby facilitating the prevention and treatment of the liver injury associated with hypothermia. METHODS: The mice were placed in a -20 °C environment, to establish a hypothermic injury model. The liver function, metabolites, and proteins expression were measured by thromboelastography, histopathology, metabolomics and western blotting, respectively. Furthermore, apoptosis and pathway changes in the liver cells conducted with target metabolites were examined and verified. RESULTS: According to the prolonged righting reflex recovery time and death occurrence, the mice with the anal temperature (AT) dropping to 20 °C or 15 °C were used to establish a model of hypothermia. The model mice showed changes in alanine aminotransferase (ALT), aspartate transaminase (AST), and coagulation indicators. HE staining results indicated that liver tissue in the AT 20°C mice had large hemorrhagic patches, while the AT 15°C mice displayed significant congestion, along with extensive infiltration of inflammatory cells around the central vein. Metabolomic and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of target metabolites revealed a significant increase in 3-hydroxybutyric acid and changes in the cyclic adenosine monophosphate (cAMP) signaling pathway in the liver tissue of hypothermic mice. The hypothermic mice showed decreases in levels of cAMP, protein kinase A C-α (PKA C-α), and phosphorylated BCL-2/BCL-XL-associated death promoter (p-Bad) and an increase in BCL-2/BCL-XL-associated death promoter (Bad) level in the liver. These protein changes and apoptosis were intensified by 3-hydroxybutyric acid in liver cells. CONCLUSION: Hypothermia may induce apoptosis in the liver cell which may be related to the changes of the cAMP-PKA pathway proteins expression. These findings provide a basis for the treatment of hypothermic injury.