Inhibition of Bone Morphogenetic Proteins Protects Against Atherosclerosis and Vascular Calcification

Yao, Yucheng; Bennett, Brian J.; Wang, Xuping; Rosenfeld, Michael E.; Giachelli, Cecilia M.; Lusis, Aldons J.; Boström, Kristina I.

doi:10.1161/circresaha.110.219071

Cited by 220 publications

(244 citation statements)

References 39 publications

(70 reference statements)

Supporting

Mentioning

231

Contrasting

Unclassified

Order By: Relevance

“…Kossa-stainable calcium deposition is nevertheless considered an acceptable surrogate for human complex lesion calcification [48]. We clearly demonstrate that uPAR deficiency reduces vascular calcification in murine atherosclerosis, a phenomenon that is much more prominent in human plaques and plays a major role in lesion destabilization.…”

Section: Discussionmentioning

confidence: 84%

Urokinase Receptor Mediates Osteogenic Differentiation of Mesenchymal Stem Cells and Vascular Calcification via the Complement C5a Receptor

Anaraki

Patecki²,

Larmann³

et al. 2014

Stem Cells and Development

View full text Add to dashboard Cite

Vascular calcification is a severe consequence of several pathological processes with a lack of effective therapy. Recent studies suggest that circulating and resident mesenchymal stem cells (MSC) contribute to the osteogenic program of vascular calcification. Molecular mechanisms underlying MSC osteogenic potential and differentiation remain, however, sparsely explored. We investigated a role for the complement receptor C5aR in these processes. We found that expression of C5aR was upregulated upon differentiation of human MSC to osteoblasts. C5aR inhibition by silencing and specific antagonist impaired osteogenic differentiation. We demonstrate that C5aR expression upon MSC differentiation was regulated by the multifunctional urokinase receptor (uPAR). uPAR targeting by siRNA resulted in complete abrogation of C5aR expression and consequently in the inhibition of MSC-osteoblast differentiation. We elucidated the NFkB pathway as the mechanism utilized by the uPAR-C5aR axis. MSC treatment with the NFkB inhibitor completely blocked the differentiation process. Nuclear translocation of the p65 RelA component of the NFkB complex was induced under osteogenic conditions and impaired by the inhibition of uPAR or C5aR. Dual-luciferase reporter assays demonstrated enhanced NFkB signaling upon MSC differentiation, whereas uPAR and C5aR downregulation lead to inhibition of the NFkB activity. We show involvement of the Erk1/2 kinase in this cascade. In vivo studies in a uPAR/LDLR double knockout mouse model of diet-induced atherosclerosis revealed impaired C5aR expression and calcification in aortic sinus plaques in uPAR -/ -/LDLR -/ -versus uPAR + / + /LDLR -/ -control animals. These results suggest that uPAR-C5aR axis via the underlying NFkB transcriptional program controls osteogenic differentiation with functional impact on vascular calcification in vivo.

show abstract

Section: Discussionmentioning

confidence: 84%

Urokinase Receptor Mediates Osteogenic Differentiation of Mesenchymal Stem Cells and Vascular Calcification via the Complement C5a Receptor

Anaraki

Patecki²,

Larmann³

et al. 2014

Stem Cells and Development

View full text Add to dashboard Cite

show abstract

“…BMP-2 and BMP-4 have been demonstrated to affect VEGF production via ALK-1/ Smad-1 signaling with concurrent effects on atherogenesis 13,28,43,44) . Despite the fact that there are no data available about statin effects on the BMP/ALK-1/Smad1/VEGF pathway, we did not study the effects of atorvastatin treatment on this signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Activation of TGF-β Receptors and Smad Proteins by Atorvastatin is Related to Reduced Atherogenesis in ApoE/LDLR Double Knockout Mice

Vecerova¹,

Strasky²,

Rathouska³

et al. 2012

JAT

View full text Add to dashboard Cite

Aim: Transforming growth factor-beta (TGF-) plays important role in atherogenesis via TGF-receptors and Smad proteins, which determine its signaling activity. In this study, we hypothesized, whether non-lipid related effects of atorvastatin, affect both endoglin/ALK-5/Smad2/eNOS and/or endoglin/ALK-1/Smad1/VEGF previously proposed pathways in ApoE/LDLR double knockout mice. Methods: ApoE/LDLR double knockout mice were divided into two groups. The chow group (CHOW) (n 8) was fed with chow diet, while in the atorvastatin group (ATV) (n 8) atorvastatin was added to the chow diet at dose 50 mg/kg/day. Biochemical analyses of lipid profile, lesion area measurement, immunohistochemistry and Western blot analysis of endoglin, ALK-1, 5, phosphorylated and non-phosphorylated forms Smad-1, 2, VEGF and eNOS proteins in mice aorta were performed. Results: Biochemical analysis of blood serum and morphometric analysis of aortic lesion size showed that atorvastatin treatment resulted in a significant increase of cholesterol levels and simultaneously in reduced lesion size in aortic sinus when compared to CHOW mice. Western blot analysis revealed that atorvastatin treatment significantly increase the expressions of endoglin by 102%, ALK-1 by 113%, ALK-5 by 296%, pSmad-1 by 202%, pSmad-2 by 34%, VEGF by 68% and eNOS by 687% as compared with CHOW mice. Immunofluorescence staining revealed endoglin coexpression with all studied markers that were increased by atorvastatin treatment mainly in endothelial cells covering atherosclerotic plaques. Conclusion: This study shows that atorvastatin treatment increases the expression of endoglin, ALK-1, ALK-5, phosphorylated forms of Smad1 and Smad2, VEGF and eNOS and reduces atherosclerotic lesion size beyond its lipid lowering effects. Therefore, we propose that endoglin related receptors and signal transducers might play protective role in atherogenesis.

show abstract

“…However, it appears that the hallmarks of calcification induced by GlaMGP deficiency are not the same as in the warfarin-induced pathology. Genetic ablation of MGP leads to VC that is associated with chondrogenic transformation of the smooth muscle (16) and is mediated by activated BMP signaling (13,14,17). In contrast, warfarin-induced calcification of elastic lamellae in vivo does not involve ectopic chondrogenesis, and ex vivo studies indicate that it may not hinge on BMP activation (11).…”

Section: Vascular Calcification (Vc)mentioning

confidence: 99%

Quercetin Attenuates Warfarin-induced Vascular Calcification in Vitro Independently from Matrix Gla Protein

Beazley

Eghtesad

Nurminskaya

2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Molecular mechanism(s) of warfarin-induced vascular calcification are not well known. Results: Inhibition of ␤-catenin signaling with shRNA or quercetin prevents osteoblastic transformation and calcification in VSMCs and calcification in aortic rings treated with warfarin, independent from MGP and protein carboxylation. Conclusion: Quercetin inhibits vascular calcification via ␤-catenin signaling. Significance: Quercetin may be instrumental in treatment of warfarin-induced vascular calcification.

show abstract

Inhibition of Bone Morphogenetic Proteins Protects Against Atherosclerosis and Vascular Calcification

Cited by 220 publications

References 39 publications

Urokinase Receptor Mediates Osteogenic Differentiation of Mesenchymal Stem Cells and Vascular Calcification via the Complement C5a Receptor

Urokinase Receptor Mediates Osteogenic Differentiation of Mesenchymal Stem Cells and Vascular Calcification via the Complement C5a Receptor

Activation of TGF-β Receptors and Smad Proteins by Atorvastatin is Related to Reduced Atherogenesis in ApoE/LDLR Double Knockout Mice

Quercetin Attenuates Warfarin-induced Vascular Calcification in Vitro Independently from Matrix Gla Protein

Contact Info

Product

Resources

About