Bone morphogenetic protein -7 increases thrombogenicity of lipid-rich atherosclerotic plaques via activation of tissue factor.
Thrombogenicity of atherosclerotic plaques largely depends on plaque morphology. Tissue factor (TF) expression is higher in lipid-rich than in calcified lesions. Although bone morphogenetic protein (BMP) -7 is a known inhibitor of vascular calcification, the role of BMP-7 in the development of plaque thrombogenicity is uncertain. We hypothesized that increased thrombogenic potential of lipid-rich plaques is attributed to activation of TF by BMP-7. We measured levels of BMP-7 and TF proteins in lipid-rich and calcified carotid plaques, and tested the effects of BMP-7 on TF expression in human monocytes in vitro. Quantitative immunohistochemical analysis of endarterectomy specimens for TF and BMP-7 revealed that lipid-rich plaques contained more TF antigen than calcified ones (158.6±25.3 vs 37.4±8.8 AU, p<0.008). Lipid-rich plaques also expressed higher levels of BMP-7 (60.7±5.2 AU) than calcified lesions (31.8±8.6 AU, p<0.021). In vitro treatment of whole blood with BMP-7 markedly increased the population of TF-positive monocytes from 1.5±0.6 % to 31.0±7.6 % (p<0.001). Stimulation of blood with BMP-7 was accompanied by elevated surface presentation of TF antigen in monocytes as TF-dependent fluorescence intensity increased from 5.0±2.6 AU in unstimulated conditions to 15.8±1.9 AU after incubation with BMP-7 (p<0.002). Our data suggest that BMP-7 contributes to increased thrombogenicity of lipid-rich plaques via enhancement of TF expression.
Sovershaev
M A
MA
Division of Internal Medicine, University Hospital of North Norway, N-9038, Tromsø, Norway. mikhail.sovershaev@uit.no
Egorina
E M
EM
Bogdanov
V Y
VY
Seredkina
N
N
Fallon
J T
JT
Valkov
A Y
AY
Østerud
B
B
Hansen
J B
JB
D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D050356:Lipid Metabolism; D009000:Monocytes / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D013927:Thrombosis / Q000209:etiology*
D055419:Bone Morphogenetic Protein 7; D013925:Thromboplastin