Bone morphogenetic protein -7 increases thrombogenicity of lipid-rich atherosclerotic plaques via activation of tissue factor

Sovershaev, M.A.; Egorina, E.M.; Bogdanov, V.Y.; Seredkina, N.; Fallon, J.T.; Valkov, A.Y.; Østerud, B.; Hansen, J.B.

doi:10.1016/j.thromres.2010.06.026

« Previous Next »Thrombosis Research
Volume 126, Issue 4 , Pages 306-310, October 2010

Bone morphogenetic protein -7 increases thrombogenicity of lipid-rich atherosclerotic plaques via activation of tissue factor

M.A. Sovershaev
- Division of Internal Medicine, University Hospital of North Norway, N-9038, Tromsø, Norway
- Hematological Research Group, Department of Clinical Medicine, The Faculty of Health Sciences, University of Tromsø, N-9037, Tromsø, Norway
- Corresponding author. Division of Internal Medicine, University Hospital of North Norway, N-9038, Tromsø, Norway. Tel.: +47 77645457.
- E.M.E. and M.A.S. contributed equally to this work.
E.M. Egorina
- Division of Internal Medicine, University Hospital of North Norway, N-9038, Tromsø, Norway
- Hematological Research Group, Department of Clinical Medicine, The Faculty of Health Sciences, University of Tromsø, N-9037, Tromsø, Norway
- E.M.E. and M.A.S. contributed equally to this work.
V.Y. Bogdanov
- University of Cincinnati College of Medicine, Department of Internal Medicine, Cincinnati, OH, 45267, USA
N. Seredkina
- Molecular Pathology Research Group, Department of Medical Biology, The Faculty of Health Sciences, University of Tromsø, N-9037, Tromsø, Norway
J.T. Fallon
- Department of Pathology, Mount Sinai School of Medicine, New York, NY, 10029, USA
A.Y. Valkov
- Department of Pathology, University Hospital of North Norway, N-9038, Tromsø, Norway
B. Østerud
- Hematological Research Group, Department of Medical Biology, The Faculty of Health Sciences, University of Tromsø, N-9037, Tromsø, Norway
J.B. Hansen
- Division of Internal Medicine, University Hospital of North Norway, N-9038, Tromsø, Norway
- Hematological Research Group, Department of Clinical Medicine, The Faculty of Health Sciences, University of Tromsø, N-9037, Tromsø, Norway

Received 3 May 2010; received in revised form 23 June 2010; accepted 30 June 2010. published online 26 July 2010.

Abstract

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.