Bone Morphogenic Proteins: Novel mediators of atherothrombosis

Most arterial cardiovascular events (myocardial infarction and stroke) occur as a consequence of atherosclerotic plaque rupture with subsequent thrombus formation at the culprit lesion. Lipid-rich plaques with a thin fibrous cap are particularly prone to plaque rupture and subsequent thrombus formation initiated by tissue factor (TF) expression. Bone morphogenic proteins (BMP1-15) regulates bone homeostasis and atherosclerosis. We hypothesized that BMP7 promotes plaque instability and plaque thrombogenicity by upregulation of TF expression in monocytes/macrophages enriched in plaques. Our results demonstrated that BMP7 levels discriminates between individuals with echogenic (calcified and stable) and echolucent (lipid-rich and thrombosis-prone) carotid plaques, suggestive of a biomarker of plaque morphology. Next, we delineated the signal pathways of BMP-dependent monocyte reactivity (tissue factor- mediated thrombogenicity and cell motility) and characterized molecular events related to transcriptional regulation of F3 (TF) gene. Lastly, we demonstrated that inhibition of the BMP signaling in monocytes ameliorated BMP-mediated monocyte reactivity, implying that BMP signaling is a targetable pathway for therapeutic interventions.

Principal Investigator: John-Bjarne Hansen

Project Members: Timophey Sovershaev, Michael Sovershaev

External Collaborators: Vladimir Bogdanov (University of Cincinnati, USA) 

Publications:

Sovershaev et al. A novel role of bone morphogenetic protein-7 in the regulation of adhesion and migration of human monocytic cells. Thromb Res 2016; 147: 24-31.

Sovershaev et al. BMP-7 induces TF expression in human monocytes by increasing F3 transcriptional activity. Thromb Res 2015; 153: 398-403.

Research council of Norway (FRIPRO grant)