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)
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