title: Genotype-dependent impairment of hemoglobin clearance increases oxidative and inflammatory response in human diabetic atherosclerosis.
abstract: OBJECTIVE
  Haptoglobin (Hp) protein is responsible for hemoglobin clearance after intra-plaque hemorrhage. Hp gene exists as Hp-1 and Hp-2 alleles and the phenotypes show important molecular heterogeneity. We tested the hypothesis that hemoglobin clearance may be deficient in diabetic atheroma from patients with Hp2-2, triggering increased oxidative, inflammatory, and angiogenic patterns compared with controls.
  
  
  RESULTS
  Forty patients with diabetes mellitus were genotyped and their peripheral plaques compared after atherectomy. Plaque hemorrhage, iron content, hemoglobin-binding protein CD163, and heme-oxygenase-1 were quantified. Oxidative, inflammatory, and angiogenic patterns were evaluated by measuring myeloperoxidase, interleukin-10, macrophages, vascular cell adhesion molecule-1, smooth muscle actin, and plaque neovascularization (CD34/CD31). Plaques with Hp2-2 (n=7) had increased hemorrhage (P<0.005), iron content (P<0.001), and reduced CD163 expression (P<0.002) compared with controls (n=14). Hp2-2 plaques had increased heme-oxygenase-1 protein (P<0.02), myeloperoxidase gene (P<0.05), and protein (P<0.0001). Anti-inflammatory interleukin-10 gene (P<0.04), and protein expressions (P<0.0001) were decreased in Hp2-2. Finally, macrophage (P<0.0001), vascular cell adhesion molecule-1 (P=0.001), smooth muscle actin (P=0.002) scores, and neovessels density (P<0.0001) were increased in Hp2-2.
  
  
  CONCLUSIONS
  Genotype-dependent impairment of hemoglobin clearance after intra-plaque hemorrhage is associated with increased oxidative, inflammatory, and angiogenic response in human diabetic atherosclerosis.
authors.affiliation: Zena and Michael A. Weiner Cardiovascular Institute and the Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1030, New York, NY 10029, USA.
authors.forename: Meerarani
authors.initials: M
authors.lastname: Purushothaman
authors.forename: Prakash
authors.initials: P
authors.lastname: Krishnan
authors.forename: K-Raman
authors.initials: KR
authors.lastname: Purushothaman
authors.forename: Usman
authors.initials: U
authors.lastname: Baber
authors.forename: Arthur
authors.initials: A
authors.lastname: Tarricone
authors.forename: Juan S
authors.initials: JS
authors.lastname: Perez
authors.forename: Jose
authors.initials: J
authors.lastname: Wiley
authors.forename: Annapoorna
authors.initials: A
authors.lastname: Kini
authors.forename: Samin K
authors.initials: SK
authors.lastname: Sharma
authors.forename: Valentin
authors.initials: V
authors.lastname: Fuster
authors.forename: Pedro R
authors.initials: PR
authors.lastname: Moreno
mesh_terms: D000199:Actins / Q000378:metabolism; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000601:surgery; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics* / Q000276:immunology; D003925:Diabetic Angiopathies / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000601:surgery; D005260:Female; D005838:Genotype; D006242:Haptoglobins / Q000235:genetics* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000235:genetics* / Q000276:immunology; D016753:Interleukin-10 / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D018384:Oxidative Stress / Q000235:genetics*; D009195:Peroxidase / Q000378:metabolism; D010641:Phenotype; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D000098902:CD163 Antigen
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D000098902:CD163 Antigen; C485359:HP protein, human; D006242:Haptoglobins; D006454:Hemoglobins; C508609:IL10 protein, human; D011956:Receptors, Cell Surface; D019010:Vascular Cell Adhesion Molecule-1; D016753:Interleukin-10; D007501:Iron; D009195:Peroxidase; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1