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Related Concept Videos

Nitric Oxide Signaling Pathway01:28

Nitric Oxide Signaling Pathway

Nitric oxide (NO), an inorganic gas, acts as a potent second messenger in most animal and plant tissues. NO diffuses out of the cells that produce it and enters the neighboring cells to generate a downstream response. NO synthase (NOS) catalyzes NO production by the deamination of the amino acid arginine. There are three isoforms of NOS. Endothelial cells have endothelial NOS (eNOS), nerve and muscle cells have neuronal NOS (nNOS), and macrophages produce inducible NOS (iNOS) upon exposure to...
Hypoxia01:23

Hypoxia

Hypoxia is a medical condition characterized by an inadequate oxygen supply to body tissues. It typically manifests as a bluish discoloration of the skin and mucosae, especially in fair-skinned individuals, when hemoglobin (Hb) saturation drops below 75%.
Types of Hypoxia
There are four primary types of hypoxia, each resulting from a different cause:
1. Anemic hypoxia: This type occurs due to insufficient oxygen delivery caused by a lack of red blood cells (RBCs) or RBCs with abnormal or...
Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
Oxygen Transport in the Blood01:27

Oxygen Transport in the Blood

Hemoglobin (Hb) is a crucial molecule in the human body, consisting of four polypeptide chains, each bound to an iron-containing heme group. This unique structure enables hemoglobin to bind to oxygen, with each molecule capable of combining with four molecules of oxygen, leading to rapid and reversible oxygen loading. When fully loaded with oxygen, it is called oxyhemoglobin, while hemoglobin that has released oxygen is called reduced hemoglobin or deoxyhemoglobin. As hemoglobin binds oxygen,...
The Electron Transport Chain01:30

The Electron Transport Chain

The electron transport chain or oxidative phosphorylation is an exothermic process in which free energy released during electron transfer reactions is coupled to ATP synthesis. This process is a significant source of energy in aerobic cells, and therefore inhibitors of the electron transport chain can be detrimental to the cell's metabolic processes.
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q in...
Paracrine Signaling01:21

Paracrine Signaling

Paracrine signaling allows cells to communicate with their immediate neighbors via secretion of signaling molecules. Such a signal can only trigger a response in nearby target cells because the signal molecules degrade quickly or are inactivated if not taken up. Prominent examples of paracrine signaling include nitric oxide signaling in blood vessels, synaptic signaling of neurons, the blood clotting system, tissue repair/wound healing, and local allergic skin reactions. Nitric oxide as a...

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En Face Detection of Nitric Oxide and Superoxide in Endothelial Layer of Intact Arteries
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Nitric oxide and superoxide: interference with hypoxic signaling.

Bernhard Brüne1, Jie Zhou

  • 1Institute of Biochemistry I, Faculty of Medicine, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. bruene@zbc.kgu.de

Cardiovascular Research
|April 7, 2007
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Summary

Nitric oxide (NO) plays a dual role in regulating cellular oxygen levels. High NO mimics hypoxia by stabilizing hypoxia-inducible factor alpha (HIF-1alpha), while low NO facilitates HIF-1alpha degradation.

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Area of Science:

  • Cellular biology
  • Physiology
  • Biochemistry

Background:

  • Cellular oxygen homeostasis is critical for preventing oxidative damage and hypoxia.
  • The hypoxia-inducible factor (HIF) pathway, involving prolyl hydroxylases (PHDs), pVHL, and the 26S proteasome, regulates cellular adaptation to oxygen levels.
  • HIF-1alpha stabilization and dimerization with HIF-1beta are essential for activating target genes.

Purpose of the Study:

  • To elucidate the complex role of nitric oxide (NO) in modulating the hypoxia-inducible factor (HIF) regulatory system.
  • To investigate how different concentrations of NO influence HIF-1alpha stability under normoxia and hypoxia.
  • To explore the interplay between NO, oxygen (O2), and superoxide (O2(-)) in regulating cellular oxygen responses.

Main Methods:

  • The study investigates the mechanisms by which NO affects the prolyl hydroxylase (PHD) activity and subsequent hydroxylation of HIF-1alpha.
  • It examines the impact of NO on the interaction between HIF-1alpha and the von Hippel-Lindau protein (pVHL).
  • The research analyzes the consequences of NO on HIF-1alpha accumulation and proteasomal degradation under varying oxygen conditions.

Main Results:

  • High concentrations of NO stabilize HIF-1alpha under normoxia by inhibiting PHDs, mimicking hypoxia.
  • Low concentrations of NO facilitate HIF-1alpha degradation during hypoxia by impairing respiration and maintaining PHD activity.
  • The signaling of NO is modulated by superoxide (O2(-)), creating a dynamic system for fine-tuning HIF-1alpha levels.

Conclusions:

  • Nitric oxide exhibits a versatile and concentration-dependent role in the HIF pathway, acting as both an activator and repressor of the hypoxic response.
  • The interaction between NO, O2, and O2(-) provides a sophisticated mechanism for cellular oxygen sensing and adaptation.
  • Understanding this intricate NO-HIF crosstalk is crucial for comprehending cellular responses to oxygen fluctuations.