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Inhibition of Bone Morphogenetic Protein Signaling Reduces Vascular Calcification and Atherosclerosis
M Derwall, R Malhotra, CS Lai... - ... and Vascular Biology, 2012 - Am Heart Assoc ObjectiveThe expression of bone morphogenetic proteins (BMPs) is enhanced in human atherosclerotic and calcific vascular lesions. Although genetic gain-and loss-of-function experiments in mice have supported a causal role of BMP signaling in atherosclerosis and ...
Methods and Results—We tested the impact of pharmacological BMP inhibition on atherosclerosis and calcification in LDL receptor-deficient (LDLR−/−) mice. LDLR−/− mice fed a high-fat diet developed abundant vascular calcification within 20 weeks. Prolonged treatment of LDLR−/− mice with the small molecule BMP inhibitor LDN-193189 was well-tolerated and potently inhibited development of atheroma, as well as associated vascular inflammation, osteogenic activity, and calcification. Administration of recombinant BMP antagonist ALK3-Fc replicated the antiatherosclerotic and anti-inflammatory effects of LDN-193189. Treatment of human aortic endothelial cells with LDN-193189 or ALK3-Fc abrogated the production of reactive oxygen species induced by oxidized LDL, a known early event in atherogenesis. Unexpectedly, treatment of mice with LDN-193189 lowered LDL serum cholesterol by 35% and markedly decreased hepatosteatosis without inhibiting HMG-Co A reductase activity. Treatment with BMP2 increased, whereas LDN-193189 or ALK3-Fc inhibited apolipoprotein B100 secretion in Hep G2 cells, suggesting that BMP signaling contributes to the regulation of cholesterol biosynthesis.
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Inhibition of Bone Morphogenetic Protein Signaling Reduces Vascular Calcification and Atherosclerosis |
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