TY - JOUR
T1 - Genotype-dependent impairment of hemoglobin clearance increases oxidative and inflammatory response in human diabetic atherosclerosis
AU - Purushothaman, Meerarani
AU - Krishnan, Prakash
AU - Purushothaman, K. Raman
AU - Baber, Usman
AU - Tarricone, Arthur
AU - Perez, Juan S.
AU - Wiley, Jose
AU - Kini, Annapoorna
AU - Sharma, Samin K.
AU - Fuster, Valentin
AU - Moreno, Pedro R.
PY - 2012/11
Y1 - 2012/11
N2 - 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. Conclusion-Genotype-dependent impairment of hemoglobin clearance after intra-plaque hemorrhage is associated with increased oxidative, inflammatory, and angiogenic response in human diabetic atherosclerosis.
AB - 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. Conclusion-Genotype-dependent impairment of hemoglobin clearance after intra-plaque hemorrhage is associated with increased oxidative, inflammatory, and angiogenic response in human diabetic atherosclerosis.
KW - Atherosclerosis
KW - Diabetes mellitus
KW - Haptoglobin
KW - Inflammation
KW - Oxidative stress
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U2 - 10.1161/ATVBAHA.112.252122
DO - 10.1161/ATVBAHA.112.252122
M3 - Article
C2 - 22982461
AN - SCOPUS:84871861524
SN - 1079-5642
VL - 32
SP - 2769
EP - 2775
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 11
ER -