Inhibition of bone morphogenetic protein signaling reduces vascular calcification and atherosclerosis.
OBJECTIVE
The 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 vascular calcification, it remains uncertain whether BMP signaling might be targeted pharmacologically to ameliorate both of these processes.


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-CoA reductase activity. Treatment with BMP2 increased, whereas LDN-193189 or ALK3-Fc inhibited apolipoprotein B100 secretion in HepG2 cells, suggesting that BMP signaling contributes to the regulation of cholesterol biosynthesis.


CONCLUSIONS
These results definitively implicate BMP signaling in atherosclerosis and calcification, while uncovering a previously unidentified role for BMP signaling in LDL cholesterol metabolism. BMP inhibition may be helpful in the treatment of atherosclerosis and associated vascular calcification.
Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, the Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. mderwall@ukaachen.de
Matthias
M
Derwall
Rajeev
R
Malhotra
Carol S
CS
Lai
Yuko
Y
Beppu
Elena
E
Aikawa
Jasbir S
JS
Seehra
Warren M
WM
Zapol
Kenneth D
KD
Bloch
Paul B
PB
Yu
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002317:Cardiovascular Agents / Q000494:pharmacology*; D008078:Cholesterol, LDL / Q000097:blood; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D061205:Vascular Calcification / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D019485:Bone Morphogenetic Proteins; D002317:Cardiovascular Agents; D008078:Cholesterol, LDL; C554430:LDN 193189; D008077:Lipoproteins, LDL; D011720:Pyrazoles; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D011973:Receptors, LDL; D011993:Recombinant Fusion Proteins; C099252:oxidized low density lipoprotein; D052005:Bone Morphogenetic Protein Receptors, Type I