Red cells, hemoglobin, heme, iron, and atherogenesis.
OBJECTIVE
We investigated whether red cell infiltration of atheromatous lesions promotes the later stages of atherosclerosis.


RESULTS
We find that oxidation of ferro (FeII) hemoglobin in ruptured advanced lesions occurs generating ferri (FeIII) hemoglobin and via more extensive oxidation ferrylhemoglobin (FeIII/FeIV=O). The protein oxidation marker dityrosine accumulates in complicated lesions, accompanied by the formation of cross-linked hemoglobin, a hallmark of ferrylhemoglobin. Exposure of normal red cells to lipids derived from atheromatous lesions causes hemolysis and oxidation of liberated hemoglobin. In the interactions between hemoglobin and atheroma lipids, hemoglobin and heme promote further lipid oxidation and subsequently endothelial reactions such as upregulation of heme oxygenase-1 and cytotoxicity to endothelium. Oxidative scission of heme leads to release of iron and a feed-forward process of iron-driven plaque lipid oxidation. The inhibition of heme release from globin by haptoglobin and sequestration of heme by hemopexin suppress hemoglobin-mediated oxidation of lipids of atheromatous lesions and attenuate endothelial cytotoxicity.


CONCLUSIONS
The interior of advanced atheromatous lesions is a prooxidant environment in which erythrocytes lyse, hemoglobin is oxidized to ferri- and ferrylhemoglobin, and released heme and iron promote further oxidation of lipids. These events amplify the endothelial cell cytotoxicity of plaque components.
Nagy
Emoke
E
Hemostasis, Thrombosis and Vascular Biology Research Group, Hungarian Academy of Sciences, Debrecen, Hungary.
Eaton
John W
JW
Jeney
Viktória
V
Soares
Miguel P
MP
Varga
Zsuzsa
Z
Galajda
Zoltán
Z
Szentmiklósi
József
J
Méhes
Gábor
G
Csonka
Tamás
T
Smith
Ann
A
Vercellotti
Gregory M
GM
Balla
György
G
Balla
József
J
D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood* / Q000473:pathology; D002470:Cell Survival; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004912:Erythrocytes / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006242:Haptoglobins / Q000378:metabolism; D006406:Hematoma / Q000097:blood* / Q000473:pathology; D006418:Heme / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000097:blood; D006454:Hemoglobins / Q000378:metabolism*; D006461:Hemolysis; D006466:Hemopexin / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000097:blood*; D015227:Lipid Peroxidation; D008077:Lipoproteins, LDL / Q000378:metabolism; D008706:Methemoglobin / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood
D006242:Haptoglobins; D006454:Hemoglobins; D008077:Lipoproteins, LDL; C517773:ferrylhemoglobin; D014443:Tyrosine; D006418:Heme; D008706:Methemoglobin; D006466:Hemopexin; C007543:dityrosine; D007501:Iron; D005979:Glutathione Peroxidase; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D005978:Glutathione