Published online before print May 24, 2007, doi: 10.1161/CIRCRESAHA.107.149435
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Submitted on January 28, 2007
Revised on May 15, 2007
Accepted on May 16, 2007
Downregulation of the Hemoglobin Scavenger Receptor in Individuals With Diabetes and the Hp 2-2 Genotype. Implications for the Response to Intraplaque Hemorrhage and Plaque Vulnerability
Andrew P. Levy *;
From the Faculty of Medicine (A.P.L., N.S.L., M.S., R.A., S.M., O.C.), Technion-Israel Institute of Technology, Haifa, Israel; the Department of Medical Biochemistry (S.K.M.), University of Aarhus, and the Department of Clinical Biochemistry (H.J.M.), AS Aarhus University Hospital, Aarhus, Denmark; and the Department of Cardiology (K.R.P., M.P., E.A.Z., D.B., V.F., P.M.), Mt Sinai Medical Center, New York.
* To whom correspondence should be addressed. E-mail: alevy{at}tx.technion.ac.il.
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 µg/mL versus 1.6±0.8 µg/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 µg/mL versus 2.3±0.2 µg/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.
Key words: diabetes mellitus • hemoglobin • macrophage • intraplaque hemorrhage • haptoglobin polymorphism
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