title: Bone morphogenetic protein -7 increases thrombogenicity of lipid-rich atherosclerotic plaques via activation of tissue factor.
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.
authors.affiliation: Division of Internal Medicine, University Hospital of North Norway, N-9038, Tromsø, Norway. mikhail.sovershaev@uit.no
authors.forename: M A
authors.initials: MA
authors.lastname: Sovershaev
authors.forename: E M
authors.initials: EM
authors.lastname: Egorina
authors.forename: V Y
authors.initials: VY
authors.lastname: Bogdanov
authors.forename: N
authors.initials: N
authors.lastname: Seredkina
authors.forename: J T
authors.initials: JT
authors.lastname: Fallon
authors.forename: A Y
authors.initials: AY
authors.lastname: Valkov
authors.forename: B
authors.initials: B
authors.lastname: Østerud
authors.forename: J B
authors.initials: JB
authors.lastname: Hansen
mesh_terms: 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*
chemical_list: D055419:Bone Morphogenetic Protein 7; D013925:Thromboplastin