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.

METHODS AND 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: Meerarani Purushothaman, Prakash Krishnan, K-Raman Purushothaman, Usman Baber, Arthur Tarricone, Juan S Perez, Jose Wiley, Annapoorna Kini, Samin K Sharma, Valentin Fuster, Pedro R Moreno
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 32 Issue 11 Pg. 2769-75 (Nov 2012) ISSN: 1524-4636 [Electronic] United States
• PMID: 22982461 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ACTA2 protein, human
• Actins
• Antigens, CD
• Antigens, Differentiation, Myelomonocytic
• Biomarkers
• CD163 antigen
• HP protein, human
• Haptoglobins
• Hemoglobins
• IL10 protein, human
• Receptors, Cell Surface
• Vascular Cell Adhesion Molecule-1
• Interleukin-10
• Iron
• Peroxidase
• HMOX1 protein, human
• Heme Oxygenase-1

Topics

• Actins (metabolism)
• Aged
• Antigens, CD (metabolism)
• Antigens, Differentiation, Myelomonocytic (metabolism)
• Atherosclerosis (blood, genetics, immunology, pathology, surgery)
• Biomarkers (metabolism)
• Case-Control Studies
• Diabetes Mellitus (blood, genetics, immunology)
• Diabetic Angiopathies (blood, genetics, immunology, pathology, surgery)
• Female
• Genotype
• Haptoglobins (genetics, metabolism)
• Heme Oxygenase-1 (metabolism)
• Hemoglobins (metabolism)
• Humans
• Inflammation (blood, genetics, immunology)
• Interleukin-10 (metabolism)
• Iron (metabolism)
• Male
• Middle Aged
• Neovascularization, Pathologic
• Oxidative Stress (genetics)
• Peroxidase (metabolism)
• Phenotype
• Prospective Studies
• Receptors, Cell Surface (metabolism)
• Vascular Cell Adhesion Molecule-1 (metabolism)