HIF1a

• hypoxia inducible factor 1a (HIF1a) is an oxygen level sensor

  • high oxygen -> low HIF1a, cells behave normally and normal amount of blood vessels
  • low oxygen -> high HIF1a, cells switch to anaerobic respiration and secrete VEGF to stimulate angiogenesis to make more blood vessels
  • more blood vessels -> more surface area to increase oxygen absorption in low oxygen environment

  
• normal/high oxygen levels (normoxia) leads to HIF1a ubiquitination and degradation

  • HPH enzyme does redox reaction with oxoglutarate and oxygen to form succinate and CO2
  • this helps HPH hydroxylate HIF1a on its proline residues (lysine gets acetylated)
  • this heavy PTM of HIF1a makes it a target for ubiquitin ligase complex which adds a polyubiquitin tail on HIF1a which is a target for proteasomes to degrade

  ***hypoxic conditions inhibit HPH from degrading HIF1a

  
• hypoxia leads to HIF1a stabilization, phosphorylation, and control gene expression

  • low oxygen levels (hypoxia) -> HIF1a gets phosphorylated and bound to ARNT (stabilizes HIF1a, prevents PTM by HPH) -> ARNT/HIF1a act as TF and forms complex with other molecules to respond to HIF1a Responsive Elements (HRE) on target genes that are positively/negatively regulated by HIF1a
  • increased expression of:
  • VEGF promotes angiogenesis
  • iNOS enzyme make NO to promote vasodilation to increase blood flow
  • GLUT and glycolytic enzymes (with lactate) to make more ATP