Fig. 5

Illustration of potential modulation of HIF regulation by caffeine. Stabilization of HIF1α/2α determined by several factors including oxygen, the activity of PHD complex and its co-factors and reactive oxygen species. HIF-1α/2α activates multiple genes involved in glycolysis, angiogenesis, vascular remodeling, cell proliferation, and erythropoiesis via nuclear transcription. Higher expression of VEGFR1 and angiopoietin-1 along with vascular remodeling following caffeine administration may normalize lung histology seen in hyperoxia-induced lung injury. Hydroxylation of prolyl hydroxylase complex inactivates HIF-1α/2α followed by ubiquitination and proteasome degradation. HSL: hormone-sensitive lipase; 2OG: 2oxyglutarate; ROS: reactive oxygen species; PHD: prolyl hydroxylase; HIF: hypoxia inducible factor; HRE: hypoxia response element; VEGFR1: vascular endothelial growth factor receptor-1; Ang-1: angiopoietin-1; BPD: bronchopulmonary dysplasia; AOE – antioxidant enzyme activity; ETC – electron transport chain; PTP: permeability transition pore (copyright – Vasantha HS Kumar, MD)