Flashcards in Heme Catabolism Deck (11):
Explain how free plasma Hb and heme are toxic to vascular endothelium.
Heme iron --> oxidative stress --> endothelial activation --> vasoocclusive events and thrombus formation
Free Hb scavenges NO --> vasoconstriction; NO acts on smooth muscle cells to generate cGMP, signaling smooth muscle contraction
Imbalance can lead to severe vasoconstriction and hypertension
Explain how heme can lead to lipid peroxidation.
Heme is hydrophobic and can intercalate into lipid bilayers --> lipid peroxidation
Can lead to structural changes in membranes
Products form adducts/crosslinks with non lipids
Disrupt membrane dependent signaling
Where does extravascular hemolysis take place?
Within macrophages of spleen and liver ("tissue macrophages" = red pulp macrophages in spleen and Kupfer cells in liver)
What does intravascular hemolysis require to scavenge hemoglobin-haptoglobin complexes?
CD163 positive marcrophages
What is haptoglobin?
Binds free Hb
Produced by hepatocytes and secreted into blood
Levels increased with inflammation and neplastic disease
Marker for hemolysis
"Antioxidant" after release into plasma --> oxy-Hb dimers bind haptoglobin tightly and sequester oxy-Hb preventing free heme and oxidative damage of heme iron
What happens when haptoglobin's buffering capacity is overwhelmed?
Hb undergoes rapid conversion to metHb, liberating heme
Heme than binds Hemopexin
What is Hemopexin?
Acute phase glycoprotein
Binds free heme
Produced by hepatocytes and secreted in blood
Levels increased with inflammation and in response to inflammatory cytokines and during heme overload
What does haptoglobin bind? What does hemopexin bind?
Haptoglobin binds free Hb
Hemopexin binds free Heme
What receptor does the Haptoglobin:Hb complex bind on macrophages? What about the Hemopexin:heme complex?
Haptoglobin:Hb binds CD163 on macrophages
Hemopexin:heme binds CD91 on macrophages
**Both are a part of intravascular hemolysis
Where is the enzyme HO-1 located?
In the ER with active site facing the cytoplasm