8_22_16 Hypoxia and HIF-1

Question 1

Hypoxia

Answer 1

reduced available oxygen reduces cell and tissue function, especially gradient from trachea to capillaries

Question 2

Normal physiological hypoxia

Answer 2

provides conditions that promote embryogenesis and wound healing, maintains pluripotency of stem cells

Question 3

Disease hypoxia

Answer 3

heart disease, cancer, stroke, COPD, many US deaths

Question 4

Causes of pathological hypoxia

Answer 4

reduced oxygen from lung disease or high altitude

localized ischemia

hypoxic tumor regions

Question 5

Altitude sickness progression with elevation

Answer 5

AMS HACE -> psychomotor impairment -> learning and spacial memory impaired -> hallucinations, cortical atrophy

Question 6

Why need oxygen

Answer 6

needed for ATP synthesis

Question 7

Adjustment to altitude

Answer 7

immediate, intermediate, long term all mediated by HIF-1

Question 8

Regulators

Answer 8

HIF TFs activate angiogenesis, anaerobic metabolism and resistance to apoptosis, facilitates oxygen delivery

Question 9

HIF structure

Answer 9

dimeric with an unstable alpha subunit and stable beta

Question 10

Regulation

Answer 10

transcriptional, translational, post-translational: promoted by mTOR pathway, also other modifications that mark it for degradation… eg prolyl hydroxylase marks HiF1 for degradation

w/ VHF mutation Hif-1 always stablized, incorrect response

Question 11

Restriction of HiF activity

Answer 11

at basically all steps toward degradation, there is something that can go differently in hypoxic conditions (ubiquitination of proteins that degrade HiF) also reduced Fe 2+ will stop this process

When Hif1 alpha reaches Hif1 beta, then transcription is promoted as a part of hypoxia response

leads to miRNA which shuts down normoxia genes promoting angiogenesis, metabolism and inflammation