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.
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.
Levy
Andrew P
AP
Technion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel. alevy@tx.technion.ac.il
Purushothaman
K Raman
KR
Levy
Nina S
NS
Purushothaman
Meerarani
M
Strauss
Merav
M
Asleh
Rabea
R
Marsh
Stuart
S
Cohen
Osher
O
Moestrup
Soren K
SK
Moller
Holger J
HJ
Zias
Elias A
EA
Benhayon
Daniel
D
Fuster
Valentin
V
Moreno
Pedro R
PR
D015703:Antigens, CD / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D003920:Diabetes Mellitus / Q000097:blood* / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D006242:Haptoglobins / Q000235:genetics* / Q000378:metabolism; D006454:Hemoglobins / Q000235:genetics* / Q000378:metabolism; D006470:Hemorrhage / Q000097:blood* / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D015994:Incidence; D008264:Macrophages / Q000378:metabolism; D009203:Myocardial Infarction / Q000097:blood* / Q000453:epidemiology / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D051116:Receptors, Scavenger / Q000037:antagonists & inhibitors / Q000097:blood* / Q000235:genetics; D000098902:CD163 Antigen
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; C485359:HP protein, human; D006242:Haptoglobins; D006454:Hemoglobins; D011956:Receptors, Cell Surface; D051116:Receptors, Scavenger