Cardioprotective effects of prolyl hydroxylase inhibitors during reperfusion in myocardial infarction: A study using cardiosphere‐derived cells

Cardiosphere-derived cells (CDCs) are a promising in vitro model for studying myocardial ischaemia-reperfusion (I-R) injury and testing potential therapeutic interventions. This study investigated the suitability of CDCs as a model for myocardial infarction (MI) and the effects of prolyl hydroxylase inhibitor (PHI) administration during reperfusion. CDCs were generated from neonatal mouse hearts and characterized by immunofluorescence, revealing a heterogeneous mixture of cardiomyocytes, smooth muscle cells, endothelial cells, and stem cells. The CDCs were subjected to oxygen-glucose deprivation (OGD) followed by reperfusion with or without the PHI dimethyloxalylglycine (DMOG). Cell viability, hypoxia-inducible factor 1-alpha (HIF-1α) accumulation, and gene expression were analysed. The results showed that DMOG administration during reperfusion reduced lactate dehydrogenase release, indicating decreased cell death. HIF-1α protein levels increased during OGD and were further stabilized by DMOG during reperfusion. The expression of HIF-1α target genes, such as vascular endothelial growth factor (Vegfa), and genes involved in regeneration and cardiac function, including connective tissue growth factor (Ctgf), cyclin D2 (Ccnd2), and beta-1 adrenergic receptor (Adrb1), was modulated by OGD and DMOG treatment. Comparisons with an in vivo mouse I-R injury model revealed similarities in gene expression patterns. In conclusion, CDCs serve as an effective in vitro model for studying I-R injury, closely resembling the in vivo situation. Furthermore, PHI administration during reperfusion reduces cell death and modulates the expression of genes involved in cardioprotection and regeneration, highlighting the potential of PHIs as a therapeutic strategy for I-R injury.