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Andrew P Levy,
K Raman Purushothaman,
Nina S Levy,
Meerarani Purushothaman,
Merav Strauss,
Rabea Asleh, Stuart Marsh,
Osher Cohen,
Soren K Moestrup,
Holger J Moller,
Elias A Zias,
Daniel Benhayon,
Valentin Fuster,
Pedro R Moreno
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ABSTRACT: In individuals with diabetes mellitus (DM), the haptoglobin (Hp) genotype is a major determinant of susceptibility to myocardial infarction. We have proposed that this is because of DM and Hp genotype-dependent differences in the response to intraplaque hemorrhage. The macrophage hemoglobin scavenging receptor CD163 plays an essential role in the clearance of hemoglobin released from lysed red blood cells after intraplaque hemorrhage. We sought to test the hypothesis that expression of CD163 is DM and Hp genotype-dependent. CD163 was quantified in plaques by immunohistochemistry, on peripheral blood monocytes (PBMs) by FACS, and as soluble CD163 (sCD163) in plasma by ELISA. In DM plaques, despite an increase in macrophage infiltration, CD163 immunoreactivity was lower, resulting in a dramatic reduction in the percentage of macrophages expressing CD163 (27+/-2% versus 70+/-2%, P=0.0001). In individuals with DM as compared with individuals without DM, the percentage of PBMs expressing CD163 was reduced (3.7+/-0.6% versus 7.1+/-0.9%, P<0.002) whereas soluble plasma CD163 was increased (2.6+/-1.1 microg/mL versus 1.6+/-0.8 microg/mL, P<0.0005). Among DM individuals, the Hp 2-2 genotype was associated with a decrease in the percentage of PBMs expressing CD163 (2.3+/-0.5% versus 5.6+/-1.3%, P=0.01) and an increase in plasma soluble CD163 (3.0+/-0.2 microg/mL versus 2.3+/-0.2 microg/mL, P=0.04). Taken together, these results demonstrate an impaired hemoglobin clearance capacity in Hp 2-2 DM individuals and may provide the key insight explaining the increased incidence of myocardial infarction in this population.
Circulation Research 08/2007; 101(1):106-10. · 9.49 Impact Factor
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Rabea Asleh, Stuart Marsh,
Mark Shilkrut,
Ofer Binah,
Julia Guetta,
Flavio Lejbkowicz,
Ben Enav,
Naim Shehadeh,
Yoram Kanter,
Orit Lache,
Osher Cohen,
Nina S Levy,
Andrew P Levy
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ABSTRACT: A major function of haptoglobin (Hp) is to bind hemoglobin (Hb) to form a stable Hp-Hb complex and thereby prevent Hb-induced oxidative tissue damage. Clearance of the Hp-Hb complex can be mediated by the monocyte/macrophage scavenger receptor CD163. We recently demonstrated that diabetic individuals homozygous for the Hp 2 allele (Hp 2-2) were at 500% greater risk of cardiovascular disease (CVD) compared with diabetic individuals homozygous for the Hp 1 allele (Hp 1-1). No differences in risk by Hp type were seen in individuals without diabetes. To understand the relationship between the Hp polymorphism and diabetic CVD, we sought to identify differences in antioxidant and scavenging functions between the Hp types and to determine how these functions were modified in diabetes. The scavenging function of Hp was assessed using rhodamine-tagged and 125I-Hp in cell lines stably transfected with CD163 and in macrophages expressing endogenous CD163. We found that the rate of clearance of Hp 1-1-Hb by CD163 is markedly greater than that of Hp 2-2-Hb. Diabetes is associated with an increase in the nonenzymatic glycosylation of serum proteins, including Hb. The antioxidant function of Hp was assessed with glycosylated and nonglycosylated Hb. We identified a severe impairment in the ability of Hp to prevent oxidation mediated by glycosylated Hb. We propose that the specific interaction between diabetes, CVD, and Hp genotype is the result of the heightened urgency of rapidly clearing glycosylated Hb-Hp complexes from the subendothelial space before they can oxidatively modify low-density lipoprotein to atherogenic oxidized low-density lipoprotein.
Circulation Research 07/2003; 92(11):1193-200. · 9.49 Impact Factor
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ABSTRACT: Late complications of diabetes mellitus (DM) are the leading cause of adult blindness and end-stage renal disease in the western world, and a major contributor to cardiovascular, cerebrovascular and peripheral vascular disease. The etiology of the development of chronic complications of DM is unclear, and several theories have been proposed to explain the mechanisms involved. Interest in the role of genetic factors predisposing individuals to the vascular complications of DM has grown enormously in recent years. The authors recently published evidence that haptoglobin phenotype may serve as a predictor of the relative risk of diabetes-related vascular disorders. Several mechanisms whereby haptoglobin phenotype may determine diabetic vascular complications are presented. First, the haptoglobin protein products of the different alleles differ in their antioxidant capacity. Second, the haptoglobin polymers present in individuals with 1-1, 2-1 or 2-2 phenotype appear to have differential sieving properties. Third, the haptoglobin types appear to differ in their immunomodulatory functions. These studies point towards haptoglobin phenotype as a new risk factor for vascular disease in diabetes. In addition to providing insight into the pathogenesis of diabetic vascular complications, these studies suggest a new therapeutic target for prevention of these diseases.
Experimental and clinical cardiology 02/2002; 7(2-3):113-9. · 0.58 Impact Factor
