Abstract 10990: Identification of a Critical Role for BMP Signaling in Atherogenesis
Introduction: Vascular calcification is a common sequela of atherosclerosis and is a predictor of adverse clinical outcomes. High levels of bone morphogenetic proteins (BMPs) have been detected in the blood vessels of patients with atherosclerosis and vascular calcification. Although BMPs can induce an osteogenic phenotype in vascular smooth muscle cells, the role of BMPs in the development of vascular calcification remains uncertain.
Hypothesis: Vascular calcification requires BMP signaling.
Methods: Adult LDL-receptor knockout mice (LDLR−/−) were fed an atherogenic diet up to 20 weeks to induce atherosclerosis and vascular calcification. Near-infrared fluorescence imaging of thoracic and abdominal aortae using a fluor-conjugated bisphosphonate probe and Von Kossa staining were used to assess ossification and calcification, respectively. Macrophage infiltration and activity were assessed by MAC2 staining and a fluor-conjugated cathepsin-substrate probe, respectively. Activity of the BMP signaling pathway was estimated immunohistochemically using an antibody directed against phosphorylated SMAD1/5/8. A selective small molecule BMP type I receptor kinase inhibitor, LDN-193189 (LDN), or recombinant BMP receptor ectodomain were used to antagonize BMP signaling.
Results: Atheromatous disease was detected in LDLr−/− mice after 6 weeks of diet and was associated with SMAD1/5/8 phosphorylation in foam cells and endothelium. After 12 weeks of diet, vascular calcific lesions developed and were again associated with phospho-SMAD1/5/8 immunoreactivity. Treatment of mice with LDN (3 mg/kg ip qd) for 20 weeks reduced vascular calcification (−41%, n=18; p<0.005) and foam cell SMAD1/5/8 immunoreactivity. Surprisingly, treatment with LDN also markedly attenuated atheroma formation (−43%, n=18; p<0.001). Treatment with recombinant BMP receptor ectodomain also reduced development of atheromatous lesions.
Conclusions: BMP signaling is essential for atherogenesis in addition to the development of vascular calcification. These findings strongly suggest the therapeutic potential of targeting BMP signaling in atherosclerosis and vascular calcification.
- © 2010 by American Heart Association, Inc.