Abstract
OBJECTIVES: To clarify the mechanism of myocardial injury associated with lipid peroxidation and the role of fatty acid binding proteins FABP3/4 during Static cold storage (SCS) of donor hearts. METHODS: Multi-omics analysis included mouse myocardial metabolomics and transcriptomics, proteomics of cardiac preservation solution in SCS injury. Lipid peroxidation was detected by malondialdehyde, transmission electron microscopy (TEM), and fluorescent probes. Lipid peroxidation antagonist MitoQ was examined by TEM. FABP3/4 were analyzed by combining the proteomic data of first perfusion serum from human donor hearts with those of mouse myocardial SCS solution. Overexpressing FABP3/4 were evaluated by detecting ROS and apoptosis via flow cytometry. snRNA-seq revealed the cellular landscape of SCS injury in pig cardiomyocytes. RESULTS: Multi-omics analysis of the SCS injury model revealed significant changes in lipid metabolism. Disturbed lipid metabolism and peroxidation were demonstrated in mouse SCS injury model and cell model. MitoQ attenuated lipid peroxidation and antagonized cardiac SCS injury. FABP3/4 were released during SCS and promoted injury in cardiomyocytes. In SCS solution, FABP3/4 expression were improved in both short-term and long-term SCS. In myocardial tissue, FABP3 expression decreased during short-term SCS and then gradually increased after long-term SCS. FABP4 expression were first upregulated and then decreased, remaining stable during long-term SCS. Pig cardiomyocytes showed low FABP3 and high FABP4 expression during short-term SCS. CONCLUSION: Disturbed lipid metabolism and peroxidation occur during SCS of hearts. FABP3/4 promote lipid uptake and aggravate SCS damage. FABP3/4 should be further investigated as potential therapeutic targets for SCS injury during heart transplantation.