Hypoxia

Question 1

What is hypoxia?

Answer 1

State of deficiency of available oxygen in the blood

Question 2

What is tissue oxygen tension?

Answer 2

Determines when a tissue becomes hypoxic - depends on oxygen demand, supply, and tissue aerobic capacity

Question 3

What is typical oxygen levels in the brain?

Answer 3

Low and non-uniform ~1-5%

Question 4

What is the typical oxygen level in the atmosphere?

Answer 4

21%

Question 5

What is the typical oxygen level in alveolar air?

Answer 5

14%

Question 6

What is the typical oxygen level in arterial blood?

Answer 6

12%

Question 7

What is the typical oxygen level in venous blood?

Answer 7

5%

Question 8

What is the typical oxygen level in tissues?

Answer 8

3%

Question 9

What is hypoxic hypoxia?

Answer 9

Decrease in amount of oxygen taken in

Question 10

What causes hypoxic hypoxia?

Answer 10

Hypoventilation from respiratory distress

Question 11

What type of hypoxia is caused by a decrease in inspired oxygen from respiratory distress?

Answer 11

Hypoxic hypoxia

Question 12

What is anemic hypoxia?

Answer 12

Decrease in amount of hemoglobin and therefore, reduced oxygen

Question 13

What causes anemic hypoxia?

Answer 13

Significant blood loss

Question 14

What type of hypoxia is caused by significant loss of hemoglobin and blood?

Answer 14

Anemic hypoxia

Question 15

What is stagnant hypoxia?

Answer 15

Low blood flow

Question 16

What causes stagnant hypoxia?

Answer 16

Local vasoconstriction or reduced cardiac output

Question 17

What type of hypoxia is caused by reduced cardiac output or local vasoconstriction?

Answer 17

Stagnant hypoxia

Question 18

What is histotoxic hypoxia?

Answer 18

Reduced oxygen due poisoning of oxidative enzymes

Question 19

What can cause histotoxic hypoxia?

Answer 19

Cyanide

Question 20

What is the physiological response to hypoxia?

Answer 20

Vasodilation of brain arteries and veins - to increase cerebral blood flow and oxygen delivery

Question 21

What is an anoxic brain injury?

Answer 21

Immediate neuronal death due to complete lack of oxygen delivery

Question 22

What is a hypoxic brain injury?

Answer 22

Gradual neuronal death due to restriction of oxygen delivery to the brain

Question 23

What are the clinical symptoms of an anoxic or hypoxic brain injury?

Answer 23

Loss of consciousness (short or long term), difficulties with speech, confusion, disorientation, facial drooping (Bell’s palsy)

Question 24

What is HIF1?

Answer 24

Hypoxia-inducible factor 1 is a transcription factor that response to decreases in oxygen

Question 25

What is the composition and structure of HIF1?

Answer 25

Heterodimer composed of two subunits: alpha and beta. Alpha is larger (120kDa) than beta (91-94kDa). Structure is helix-loop-helix.

Question 26

Which HIF1 subunit is present in all cells?

Answer 26

HIF1b

Question 27

Which HIF1 subunit does not respond to changes in oxygen tension?

Answer 27

HIF1b

Question 28

What is HIF1b essential for?

Answer 28

Hypoxia-induced transcriptional changes mediated by HIF1 heterodimer

Question 29

Under what conditions do HIF1a levels rise exponentially?

Answer 29

Hypoxic

Question 30

How is HIF1a usually produced/degradaded and how does this change under hypoxic conditions?

Answer 30

Made continuously and rapidly degraded during normoxia. Accumulates in hypoxic cells.

Question 31

What genes are targeted by HIF1 and what do they do?

Answer 31

Facilitate acclimatization to low oxygen: - vasomotor control - angiogenesis - iron metabolism - cell proliferation - cell death - energy metabolism

Question 32

How is HIF1a inactivated at normal oxygen levels?

Answer 32

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

Question 33

How does hypoxia activate HIF1a?

Answer 33

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

Question 34

What other factors can regulate HIF1 activity?

Answer 34

Inhibition of oxphos Accumulation of Krebs cycle metabolites PI3K/Akt/mTOR axis

Question 35

What effect does inactivation of HIF1a have on the brain?

Answer 35

Impaired learning, decreased neurogenesis, and neurodegeneration during normoxia Increased brain damage and decreased survival following hypoxia

Question 36

What cell types can HIF1a expression be induced in?

Answer 36

Neurons Astrocytes Ependymal cells Endothelial cells Microglia

Question 37

What roles does HIF1a have in embryonic development?

Answer 37

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

Question 38

What effect does HIF1a accumulation have immediately after hypoxic injury? (Within 24h)

Answer 38

Promotes cell death

Question 39

What effect does HIF1a have in the later stages of hypoxic injury? (Up to a few days)

Answer 39

Pro-survival effect by limiting the infarct size

Question 40

Which HIF1 target genes induce vasodilation?

Answer 40

NOS2 and adrenomedullin

Question 41

What do NOS2 and adrenomedullin (HIF1 target genes) do?

Answer 41

Induce vasodilation

Question 42

Which HIF1 target genes mediate angiogenesis?

Answer 42

VEGF, FLT1, and PAI1

Question 43

What do HIF1 target genes, VEGF, FLT1, and PAI1, do?

Answer 43

Mediate angiogenesis

Question 44

Which HIF1 target genes increase glucose transport and glucose/lactate metabolism?

Answer 44

GLUT1 and glycolytic enzymes

Question 45

Which HIF1 target gene protects against cerebral ischemia?

Answer 45

Erythropoietin

Question 46

How did the pharmacological block of HIF1 suppressors show the neuroprotective effects of HIF1a mediated signaling?

Answer 46

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

Question 47

What is hypoxia-induced tolerance?

Answer 47

Brief period of hypoxia that protects against otherwise lethal insult

Question 48

How was hypoxia-induced tolerance shown to be neuroprotective in animal models?

Answer 48

Animals exposed to sublethal hypoxia (8% oxygen) for 3 hours were resistant to cerebral hypoxic-ischemic insult 24h later

Question 49

What is the molecular basis of hypoxia-induced tolerance to brain ischemia?

Answer 49

Hypoxic induction of HIF1 and its target genes that induce neuroprotective effects