Hypoxia Flashcards
What is hypoxia?
State of deficiency of available oxygen in the blood
What is tissue oxygen tension?
Determines when a tissue becomes hypoxic - depends on oxygen demand, supply, and tissue aerobic capacity
What is typical oxygen levels in the brain?
Low and non-uniform ~1-5%
What is the typical oxygen level in the atmosphere?
21%
What is the typical oxygen level in alveolar air?
14%
What is the typical oxygen level in arterial blood?
12%
What is the typical oxygen level in venous blood?
5%
What is the typical oxygen level in tissues?
3%
What is hypoxic hypoxia?
Decrease in amount of oxygen taken in
What causes hypoxic hypoxia?
Hypoventilation from respiratory distress
What type of hypoxia is caused by a decrease in inspired oxygen from respiratory distress?
Hypoxic hypoxia
What is anemic hypoxia?
Decrease in amount of hemoglobin and therefore, reduced oxygen
What causes anemic hypoxia?
Significant blood loss
What type of hypoxia is caused by significant loss of hemoglobin and blood?
Anemic hypoxia
What is stagnant hypoxia?
Low blood flow
What causes stagnant hypoxia?
Local vasoconstriction or reduced cardiac output
What type of hypoxia is caused by reduced cardiac output or local vasoconstriction?
Stagnant hypoxia
What is histotoxic hypoxia?
Reduced oxygen due poisoning of oxidative enzymes
What can cause histotoxic hypoxia?
Cyanide
What is the physiological response to hypoxia?
Vasodilation of brain arteries and veins - to increase cerebral blood flow and oxygen delivery
What is an anoxic brain injury?
Immediate neuronal death due to complete lack of oxygen delivery
What is a hypoxic brain injury?
Gradual neuronal death due to restriction of oxygen delivery to the brain
What are the clinical symptoms of an anoxic or hypoxic brain injury?
Loss of consciousness (short or long term), difficulties with speech, confusion, disorientation, facial drooping (Bell’s palsy)
What is HIF1?
Hypoxia-inducible factor 1 is a transcription factor that response to decreases in oxygen
What is the composition and structure of HIF1?
Heterodimer composed of two subunits: alpha and beta. Alpha is larger (120kDa) than beta (91-94kDa). Structure is helix-loop-helix.
Which HIF1 subunit is present in all cells?
HIF1b
Which HIF1 subunit does not respond to changes in oxygen tension?
HIF1b
What is HIF1b essential for?
Hypoxia-induced transcriptional changes mediated by HIF1 heterodimer
Under what conditions do HIF1a levels rise exponentially?
Hypoxic
How is HIF1a usually produced/degradaded and how does this change under hypoxic conditions?
Made continuously and rapidly degraded during normoxia. Accumulates in hypoxic cells.
What genes are targeted by HIF1 and what do they do?
Facilitate acclimatization to low oxygen:
- vasomotor control
- angiogenesis
- iron metabolism
- cell proliferation
- cell death
- energy metabolism
How is HIF1a inactivated at normal oxygen levels?
Oxygen and 2-oxoglutarate activate prolyl-hydroxylases. CO2 and succinate are formed and prolines in HIF1a are hydroxylated
ARD1 activates lysine in HIF1a and von Hippel Lindau protein binds to the hydroxylated HIF1a with elongin C, elongin B, RBX1, and Cullin 2. This forms an E3 ubiquitin ligase that poly-ubiquitylates HIF1a and marks it for degradation in the proteasome
How does hypoxia activate HIF1a?
HIF1a is phosphorylated and binds to ARNT to form a dimer which binds to p300/CBP which then binds hypoxia response elements in HIF target genes, activating transcription
What other factors can regulate HIF1 activity?
Inhibition of oxphos
Accumulation of Krebs cycle metabolites
PI3K/Akt/mTOR axis
What effect does inactivation of HIF1a have on the brain?
Impaired learning, decreased neurogenesis, and neurodegeneration during normoxia
Increased brain damage and decreased survival following hypoxia
What cell types can HIF1a expression be induced in?
Neurons
Astrocytes
Ependymal cells
Endothelial cells
Microglia
What roles does HIF1a have in embryonic development?
Necessary for normal brain development.
Deficient mice have hydrocephalus, reduced neural cells, and impaired spatial memory. Effects rescued by in vivo delivery of HIF1a gene to embryos
What effect does HIF1a accumulation have immediately after hypoxic injury? (Within 24h)
Promotes cell death
What effect does HIF1a have in the later stages of hypoxic injury? (Up to a few days)
Pro-survival effect by limiting the infarct size
Which HIF1 target genes induce vasodilation?
NOS2 and adrenomedullin
What do NOS2 and adrenomedullin (HIF1 target genes) do?
Induce vasodilation
Which HIF1 target genes mediate angiogenesis?
VEGF, FLT1, and PAI1
What do HIF1 target genes, VEGF, FLT1, and PAI1, do?
Mediate angiogenesis
Which HIF1 target genes increase glucose transport and glucose/lactate metabolism?
GLUT1 and glycolytic enzymes
Which HIF1 target gene protects against cerebral ischemia?
Erythropoietin
How did the pharmacological block of HIF1 suppressors show the neuroprotective effects of HIF1a mediated signaling?
Inhibition or deletion of the suppressor PHD2 showed increased HIF1a levels and:
- Increased cellular expression of erythropoietin and VEGF (angiogenesis and protection against ischemia)
- Increased neurogenesis in hippocampus
- Improved cognitive function in mice suffering from chronic hypoperfusion
What is hypoxia-induced tolerance?
Brief period of hypoxia that protects against otherwise lethal insult
How was hypoxia-induced tolerance shown to be neuroprotective in animal models?
Animals exposed to sublethal hypoxia (8% oxygen) for 3 hours were resistant to cerebral hypoxic-ischemic insult 24h later
What is the molecular basis of hypoxia-induced tolerance to brain ischemia?
Hypoxic induction of HIF1 and its target genes that induce neuroprotective effects
