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1. D1: Extreme environments > S1. HIF and Oxygen Sensing > Flashcards

S1. HIF and Oxygen Sensing Flashcards

1
Q

What experiment first demonstrated a ‘humoral’ factor inducing erythropoiesis?

A

Blood from hypoxic/anaemic rabbits was transferred into normal rabbits, causing erythrocytosis in the latter

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2
Q

What discovery linked hypoxia to erythropoiesis?

A

The identification of the Erythropoietin (EPO) gene, showing EPO production is induced under hypoxic conditions

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3
Q

How was the EPO-producing cell type identified in the kidney?

A

Using transgenic mouse models expressing tagged EPO, identifying interstitial fibroblasts as the producers

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4
Q

Which cell lines enabled molecular dissection of the HIF pathway?

A

Hep3B and HepG2 hepatoma cell lines, which showed hypoxic EPO induction

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5
Q

What region of the EPO gene is critical for hypoxic regulation?

A

The Hypoxia Response Element (HRE) adjacent to the EPO gene

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6
Q

How was HIF first identified?

A

By analyzing proteins binding to the HRE, leading to the discovery of HIF as a heterodimer of alpha and beta subunits

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7
Q

What mutation analysis helped explain HIF regulation by oxygen?

A

Mutations in the oxygen-dependent degradation domain (ODDD) showed its importance for HIF stabilization in hypoxia

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8
Q

What role does the nematode C. elegans play in HIF research?

A

It helped identify Egl-9, the prolyl hydroxylase responsible for HIF regulation, due to its simpler genetic system

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9
Q

How do PHD enzymes regulate HIF?

A

They hydroxylate prolines on HIF-alpha in normoxia, marking it for degradation by VHL

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10
Q

What is the role of FIH in HIF regulation?

A

FIH hydroxylates asparagine residues on HIF-alpha, preventing co-activator binding and limiting transcription in normoxia

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11
Q

What distinguishes HIF-1alpha and HIF-2alpha?

A

HIF-1alpha is ubiquitous and essential for embryonic development, while HIF-2alpha specializes in adult hypoxic responses like erythropoiesis

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12
Q

What experiment showed HIF-2alpha’s role in erythropoiesis?

A

Transgenic mice lacking HIF-2alpha failed to show hypoxia-induced erythropoiesis

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13
Q

How is the carotid body involved in hypoxia responses?

A

It senses arterial oxygen drops, triggering acute ventilatory responses through Type I cell neurotransmitter release

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14
Q

What role does HIF-2alpha play in the carotid body?

A

It mediates chronic hypoxia-induced carotid body proliferation and ventilatory acclimatization

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15
Q

What is the link between VHL mutations and cancer?

A

VHL mutations lead to constitutive HIF activation, promoting tumors like renal clear cell carcinoma

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16
Q

How do high-altitude populations demonstrate adaptation to hypoxia?

A

Genetic studies reveal SNPs in HIF-2alpha and PHD2, associated with reduced erythrocytosis and pulmonary hypertension

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17
Q

What are PHIs and their clinical significance?

A

Prolyl hydroxylase inhibitors enhance erythropoiesis and are used to treat renal anemia, with potential for other ischemic conditions

18
Q

What is the mechanism of action for HIF-2alpha antagonists?

A

They block dimerization of HIF-2alpha with HIF-beta, inhibiting its transcriptional activity

19
Q

How did experiments with reporter constructs demonstrate HIF ubiquity?

A

Transfection of HRE-reporter genes into various cell types showed hypoxia responsiveness across diverse tissues

20
Q

What experiment linked mitochondrial adaptations to HIF-2alpha?

A

HIF-2alpha was shown to induce atypical mitochondrial subunits like Cox4i2, enhancing oxygen sensing under hypoxia

21
Q

How might HIF pathways impact COVID-19?

A

PHIs activating HIF-1alpha impair SARS-CoV-2 infection and replication, suggesting therapeutic potential

22
Q

What does the term ‘pseudohypoxia’ describe?

A

Constitutive activation of HIF due to mutations, mimicking hypoxic conditions

23
Q

What is the role of angiogenesis in hypoxia adaptation?

A

It involves the formation of new blood vessels, mediated by HIF-induced VEGF expression, to enhance oxygen delivery

24
Q

Which tumors are commonly associated with VHL mutations?

A

Renal clear cell carcinomas, hemangioblastomas, and pheochromocytomas

25
Q

What adaptation allows Tibetans to thrive at high altitudes?

A

Genetic SNPs in HIF-2alpha reduce erythrocytosis and enhance oxygen delivery efficiency

26
Q

What is the role of HIF in pulmonary hypertension?

A

HIF contributes to vascular remodeling and vasoconstriction, leading to increased pulmonary arterial pressure

27
Q

How does HIF affect glucose metabolism?

A

HIF induces glycolytic enzymes and glucose transporters, facilitating anaerobic metabolism under hypoxia

28
Q

What are atypical mitochondrial subunits induced by HIF?

A

Subunits like Cox4i2 enhance mitochondrial oxygen sensing and efficiency under hypoxia

29
Q

What experiment linked VHL to HIF regulation?

A

VHL-deficient renal carcinoma cells showed constitutive HIF activation, revealing VHL’s role in HIF degradation

30
Q

How does chronic hypoxia affect ventilatory response?

A

It leads to ventilatory acclimatization, mediated by HIF-2alpha and carotid body adaptations

31
Q

What is the primary function of PHIs in therapy?

A

To treat anemia by enhancing erythropoiesis via HIF stabilization

32
Q

What are the two classes of HIF pharmacological modulators?

A

Prolyl hydroxylase inhibitors (PHIs) and HIF-2alpha antagonists

33
Q

What is the main conclusion from hypoxia chamber studies?

A

HIF-2alpha, not HIF-1alpha, is essential for ventilatory acclimatization and carotid body proliferation

34
Q

What are the main differences between HIF-1 and HIF-2?

A

HIF-1 is involved in general metabolic adaptation, while HIF-2 specializes in systemic oxygen control

35
Q

How do genetic lineage tracers help in hypoxia studies?

A

They track progenitor cell proliferation and differentiation under hypoxic conditions

36
Q

What is Monge’s disease?

A

Chronic mountain sickness characterized by excessive erythrocytosis and pulmonary hypertension

37
Q

How do PHD inhibitors work?

A

They inhibit prolyl hydroxylase enzymes, stabilizing HIF to mimic hypoxic conditions therapeutically

38
Q

What role does the carotid body play in acute oxygen sensing?

A

It triggers immediate respiratory responses via neurotransmitter release from Type I cells

39
Q

How is the HIF pathway evolutionary conserved?

A

It is found across species, from nematodes to humans, highlighting its fundamental role in oxygen sensing

40
Q

What is the clinical significance of Belzutifan?

A

A HIF-2alpha antagonist used to treat VHL-associated renal carcinomas and pulmonary hypertension

41
Q

What does hypoxia-induced proliferation in the carotid body indicate?

A

It is a hallmark of chronic hypoxia adaptation, mediated by HIF-2alpha

1. D1: Extreme environments (6 decks)

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