Molecular mechanisms, including oxidative stress and mitochondria

11 important questions on Molecular mechanisms, including oxidative stress and mitochondria

When does Cardiac ischemia occur?

Cardiac (or Myocardial) ischemia occurs when blood flow to your heart is reduced, preventing the heart muscle from receiving enough oxygen. The reduced blood flow is usually the result of a partial or complete blockage of your heart's arteries (coronary arteries)

Name a Cardiac reperfusion (an operation)

Percutaneous coronary intervention (PCI)

Most of the energy utilised by the normal heart is derived from:

Fat

It needs a lot of energy and fat = 37 kJ/g
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Which one can be only metabolised in a well-oxygenated adult heart?

  1. Fat
  2. Carbohydrate

1. Fat

The molecular pathway in response to ischemia/hypoxia

  • Several transcription factors regulate the response to ischemia/hypoxia
  • the is a physiological response to promote survival and to restore oxygen delivery
  • hypoxia inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis
  • Dimer
    • HIF (HIF alpha) - regulated
    • ARNT (HIF beta) - constitutive

What is the main role of HIF?

Is to restore O2 supply/adapt to low O2

How are the HIF alpha's regulated? (Hypoxia)

Afbeelding

The stability of HIF is regulated by the molecular oxygen sensors EGLNs and HIF1AN

EGLN and HIF1AN regulate HIF1A

Hydroxylation reaction is dependent on oxygen

normoxia: Oxygen, hydroxylation, degradation

hypoxia: No oxygen, no hydroxylation, no degradation

Normoxia: role of EGLNs and HIF1AN (6 steps)

Image

Hypoxia (and other inhibiting conditions)

Afbeelding

EGLNs and HIF1AN are dependent on ...(4) And are inhibited by ...(6)

Function of EGLNs and HIF1AN critically depend on
  • Oxygen
  • Fe2+
  • 2-oxoglutarate
  • Ascorbate

EGLNs and HIF1AN are inhibited by
  • Lack of oxygen
  • Reactive oxygen species
  • Fumarate
  • Succinate
  • Iron chelators
  • Co2+

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