Metabolism-related gene PDK1 regulates myocardial cell remodeling and its mechanism.

The progression of ischemic heart disease results from various forms of cardiomyopathies, which begin with cardiac remodelling. Pyruvate Dehydrogenase Kinase 1 (PDK1) is one of the basic kinase family components responsible for oxidative phosphorylation. However, due to the lack of a suitable research model, there is no evidence that remodelling pathogenesis in humans causes death by PDK1 knockout (KO). In the current study, we established a PDK1-deficient human cardiomyocyte (CM) model under conditions imitating the human PDK1-KO model. We determined the role of PDK1 in myocardial apoptosis induced by hypoxia and its implicit mechanism. A human PDK1-KO CM's model was established by combining CRISPR/Cas-9 gene-editing and human induced pluripotent stem cells (hiPSC) directed differentiation technology. The pathological features of PDK1-KO cardiomyocytes were assessed using a phenotypic cell model under basal and hypoxic conditions. We found that pluripotency and differentiation efficiency of hiPSCs after PDK1 knockout remain intact. Cardiomyocytes with a PDK1 gene knockout showed hypoxia-induced myocardial apoptosis by disturbing mitochondrial metabolism, increased oxidative stress levels, and decreased cell energy and viability. In addition, lentivirus transfection significantly improved the metabolism and cell viability in PDK1-deficient cardiomyocytes. Our study established a PDK1 knockout model under hypoxia that exhibits mitochondrial metabolism dysregulation, elevated oxidative stress, and decreased cell viability. This model is an important tool for understanding the mechanism of hypoxia-induced myocardial apoptosis, elucidating the gene-phenotype relationship of PDK1 deficiency, and providing evidence to mitigate the damage against hypoxia.