High-density Lipoproteins Rescue Diabetes-impaired Angiogenesis by Restoring Cellular Metabolic Reprogramming Responses to Hypoxia

The Role of High-Density Lipoproteins in Endothelial Cell Metabolism and Diabetes-Impaired Angiogenesis

“…Furthermore, our research group has recently determined that PDK4, which inhibits mitochondrial respiration, is a target of rHDL. In human coronary artery endothelial cells, we have demonstrated that PDK4 expression is increased in hypoxia, but that this induction is impaired by exposure to high glucose conditions [50]. This aligns with the impairment to HIF-1α signalling seen under diabetic conditions in previous studies.…”

“…When the oxygen consumption of the cells was examined as a measure of mitochondrial respiration, it was found that high glucose significantly increased oxygen consumption, but that pre-incubation with rHDL was able to return these levels to the baseline. These effects were also associated with the rescue of high glucose-impaired endothelial cell migration and tubulogenesis under hypoxic conditions [50]. We, therefore, propose that rHDL augments metabolic reprogramming via the upregulation of PDK4, decreasing oxygen consumption and potentially protecting the cells against the development of oxidative stress in hypoxia.…”

“…Recent studies by our group show that, importantly, this induction is impaired when the endothelial cells are exposed to high glucose, indicating a failure of the metabolic reprogramming response. These changes were also associated with a marked increase in mitochondrial respiration, which is a known source of ROS, as well as impaired in vitro angiogenesis [50].…”

“…Consistent with this, our group has demonstrated that PDK4 was increased in human coronary artery endothelial cells (HCAECs) exposed to hypoxia. Furthermore, PDK4 knockdown by short interfering RNA (siRNA) significantly impaired endothelial cell tubule formation and migration in vitro [50]. This indicated that suppression of glucose-driven mitochondrial respiration might be essential for maintaining the endothelial cell capacity for angiogenesis, potentially by decreasing mitochondrial production of ROS or allowing for compensatory increases in fatty acid oxidation (Figure 3).…”