Diabetic cardiomyopathy is a common consequence of diabetes and associated with mitochondrial pathology. Using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) as an in vitro model of diabetes, we sought to understand the role of mitophagy, a process that selectively degrades mitochondria through the autophagy-lysosome pathway as a crucial quality control pathway against diabetic cardiomyopathy. We first showed that iPSC-CMs exposed to a diabetic milieu demonstrated increased hypertrophy, impaired calcium signaling, and higher oxidative stress. Flow cytometry analysis of iPSC-CMs subjected to diabetic conditions revealed two distinct population of cells (normal and hypertrophied), suggesting a heterogeneous response to hyperglycemia. In these cells, hypertrophied iPSC-CMs were found to have reduced mitophagy compared to normal cells when exposed to hyperglycemia. In addition, we showed that mitochondrial fragmentation was also decreased in the hypertrophied iPSC-CMs compared to normal cells upon exposure to hyperglycemia, demonstrating a link between mitochondrial fragmentation and mitophagy. Surprisingly, pretreatment of iPSC-CMs with a non-selective antioxidant, N-(2-mercaptopropionyl)-glycine, not only failed to limit the deleterious effects of hyperglycemia, but actually led to increased hypertrophy and cell death. We found that mitophagy was significantly reduced in iPSC-CMs following antioxidant treatment, suggesting the need of mild oxidative stress as a trigger for mitophagy. Future studies are warranted to further investigate the association between oxidative stress, mitochondrial fragmentation, and mitochondrial fission as targets against diabetic cardiomyopathy.
Design, Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity
