Endothelial protection through the activation of PKM2
Document Type
Event
Faculty Mentor
Igor Prudovsky
Abstract
Burn-induced trauma triggers endothelial dysfunction characterized by a surge in reactive oxygen species (ROS) and a pathological increase in vascular permeability. We have demonstrated that the popular antifibrinolytic agent tranexamic acid (TXA) significantly reduces vascular permeability after severe burn and directly binds pyruvate kinase M2 (PKM2), facilitating mitochondrial activation. This led us to evaluate the molecule TEPP-46, a potent specific PKM2 activator as a vehicle to protect endothelium. Confocal microscopy studies demonstrated that TEPP-46 enhances the staining of endothelial cell mitochondria with Mitotracker reflecting their activation and/or enhanced biogenesis. TEPP-46 treatment resulted in upregulation of a key antioxidant gene HMOX1 and greater expression of mitochondrial genes COX1 and CYTB in endothelial cells. It also increased the expression of gene METRNL coding for a hormone-like stimulator of metabolism. TEPP-46 combined with insulin improved the survival of endothelial cells devoid of FGF and VEGF. These data are in agreement with our studies on severely burned rats demonstrating that TEPP-46 suppresses the burn-induced leakage of lung endothelium. Our results suggest that TEPP-46 stabilizes the endothelium through mitochondria activation.
Endothelial protection through the activation of PKM2
Burn-induced trauma triggers endothelial dysfunction characterized by a surge in reactive oxygen species (ROS) and a pathological increase in vascular permeability. We have demonstrated that the popular antifibrinolytic agent tranexamic acid (TXA) significantly reduces vascular permeability after severe burn and directly binds pyruvate kinase M2 (PKM2), facilitating mitochondrial activation. This led us to evaluate the molecule TEPP-46, a potent specific PKM2 activator as a vehicle to protect endothelium. Confocal microscopy studies demonstrated that TEPP-46 enhances the staining of endothelial cell mitochondria with Mitotracker reflecting their activation and/or enhanced biogenesis. TEPP-46 treatment resulted in upregulation of a key antioxidant gene HMOX1 and greater expression of mitochondrial genes COX1 and CYTB in endothelial cells. It also increased the expression of gene METRNL coding for a hormone-like stimulator of metabolism. TEPP-46 combined with insulin improved the survival of endothelial cells devoid of FGF and VEGF. These data are in agreement with our studies on severely burned rats demonstrating that TEPP-46 suppresses the burn-induced leakage of lung endothelium. Our results suggest that TEPP-46 stabilizes the endothelium through mitochondria activation.
