Haptoglobin genotype is a determinant of iron, lipid peroxidation, and macrophage accumulation in the atherosclerotic plaque.
OBJECTIVE
Intraplaque hemorrhage increases the risk of plaque rupture and thrombosis. The release of hemoglobin (Hb) from extravasated erythrocytes at the site of hemorrhage leads to iron deposition, which may increase oxidation and inflammation in the atherosclerotic plaque. The haptoglobin (Hp) protein is critical for protection against Hb-induced injury. Two common alleles exist at the Hp locus and the Hp 2 allele has been associated with increased risk of myocardial infarction. We have demonstrated decreased anti-oxidative and anti-inflammatory activity for the Hp 2 protein. We tested the hypothesis that the Hp 2-2 genotype is associated with increased oxidative and macrophage accumulation in atherosclerotic plaques.


RESULTS
The murine Hp gene is a type 1 Hp allele. We created a murine type 2 Hp allele and targeted its insertion to the Hp locus by homologous recombination. Atherosclerotic plaques from C57Bl/6 ApoE-/- Hp 2-2 mice were associated with increased iron (P=0.008), lipid peroxidation (4-hydroxynonenal and ceroid) and macrophage accumulation (P=0.03) as compared with plaques from C57Bl/6 ApoE-/- Hp 1-1 mice.


CONCLUSIONS
Increased iron, lipid peroxidation and macrophage accumulation in ApoE-/- Hp 2-2 plaques suggests that the Hp genotype plays a critical role in the oxidative and inflammatory response to intraplaque hemorrhage.
Levy
Andrew P
AP
Technion Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. alevy@tx.technion.ac.il
Levy
Joanne E
JE
Kalet-Litman
Shiri
S
Miller-Lotan
Rachel
R
Levy
Nina S
NS
Asaf
Roy
R
Guetta
Julia
J
Yang
Chingwen
C
Purushothaman
K Raman
KR
Fuster
Valentin
V
Moreno
Pedro R
PR
D000483:Alleles; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016893:Carotid Stenosis / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D005838:Genotype; D006242:Haptoglobins / Q000235:genetics* / Q000378:metabolism; D006470:Hemorrhage; D007501:Iron / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D012307:Risk Factors; D012421:Rupture / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D012422:Rupture, Spontaneous
D001057:Apolipoproteins E; D006242:Haptoglobins; D007501:Iron