The nuclear hormone receptor PPARγ counteracts vascular calcification by inhibiting Wnt5a signalling in vascular smooth muscle cells

Estelle Woldt; Jérome Terrand; Mohamed Mlih; Rachel L. Matz; Véronique Bruban; Fanny Coudane; Sophie Foppolo; Zeina El Asmar; Maria Eugenia Chollet; Ewa Ninio; Audrey Bednarczyk; Danièle Thiersé; Christine Schaeffer; Alain Van Dorsselaer; Christian Boudier; Walter Wahli; Pierre Chambon; Daniel Metzger; Joachim Herz; Philippe Boucher

doi:10.1038/ncomms2087

The nuclear hormone receptor PPARγ counteracts vascular calcification by inhibiting Wnt5a signalling in vascular smooth muscle cells

Estelle Woldt, Jérome Terrand, Mohamed Mlih, Rachel L. Matz, Véronique Bruban, Fanny Coudane, Sophie Foppolo, Zeina El Asmar, Maria Eugenia Chollet, Ewa Ninio, Audrey Bednarczyk, Danièle Thiersé, Christine Schaeffer, Alain Van Dorsselaer, Christian Boudier, Walter Wahli, Pierre Chambon, Daniel Metzger, Joachim Herz, Philippe Boucher

Research output: Contribution to journal › Article › peer-review

64 Scopus citations

Abstract

Vascular calcification is a hallmark of advanced atherosclerosis. Here we show that deletion of the nuclear receptor PPARγ in vascular smooth muscle cells of low density lipoprotein receptor (LDLr)-deficient mice fed an atherogenic diet high in cholesterol, accelerates vascular calcification with chondrogenic metaplasia within the lesions. Vascular calcification in the absence of PPARγ requires expression of the transmembrane receptor LDLr-related protein-1 in vascular smooth muscle cells. LDLr-related protein-1 promotes a previously unknown Wnt5a-dependent prochondrogenic pathway. We show that PPARγ protects against vascular calcification by inducing the expression of secreted frizzled-related protein-2, which functions as a Wnt5a antagonist. Targeting this signalling pathway may have clinical implications in the context of common complications of atherosclerosis, including coronary artery calcification and valvular sclerosis.

Original language	English (US)
Article number	1077
Journal	Nature communications
Volume	3
DOIs	https://doi.org/10.1038/ncomms2087
State	Published - 2012

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

Access to Document

10.1038/ncomms2087

Cite this

Woldt, E., Terrand, J., Mlih, M., Matz, R. L., Bruban, V., Coudane, F., Foppolo, S., El Asmar, Z., Chollet, M. E., Ninio, E., Bednarczyk, A., Thiersé, D., Schaeffer, C., Van Dorsselaer, A., Boudier, C., Wahli, W., Chambon, P., Metzger, D., Herz, J., & Boucher, P. (2012). The nuclear hormone receptor PPARγ counteracts vascular calcification by inhibiting Wnt5a signalling in vascular smooth muscle cells. Nature communications, 3, [1077]. https://doi.org/10.1038/ncomms2087

Woldt, E, Terrand, J, Mlih, M, Matz, RL, Bruban, V, Coudane, F, Foppolo, S, El Asmar, Z, Chollet, ME, Ninio, E, Bednarczyk, A, Thiersé, D, Schaeffer, C, Van Dorsselaer, A, Boudier, C, Wahli, W, Chambon, P, Metzger, D, Herz, J & Boucher, P 2012, 'The nuclear hormone receptor PPARγ counteracts vascular calcification by inhibiting Wnt5a signalling in vascular smooth muscle cells', Nature communications, vol. 3, 1077. https://doi.org/10.1038/ncomms2087

@article{c25452e670d3446ba1aad2224a29bc87,

title = "The nuclear hormone receptor PPARγ counteracts vascular calcification by inhibiting Wnt5a signalling in vascular smooth muscle cells",

abstract = "Vascular calcification is a hallmark of advanced atherosclerosis. Here we show that deletion of the nuclear receptor PPARγ in vascular smooth muscle cells of low density lipoprotein receptor (LDLr)-deficient mice fed an atherogenic diet high in cholesterol, accelerates vascular calcification with chondrogenic metaplasia within the lesions. Vascular calcification in the absence of PPARγ requires expression of the transmembrane receptor LDLr-related protein-1 in vascular smooth muscle cells. LDLr-related protein-1 promotes a previously unknown Wnt5a-dependent prochondrogenic pathway. We show that PPARγ protects against vascular calcification by inducing the expression of secreted frizzled-related protein-2, which functions as a Wnt5a antagonist. Targeting this signalling pathway may have clinical implications in the context of common complications of atherosclerosis, including coronary artery calcification and valvular sclerosis.",

author = "Estelle Woldt and J{\'e}rome Terrand and Mohamed Mlih and Matz, {Rachel L.} and V{\'e}ronique Bruban and Fanny Coudane and Sophie Foppolo and {El Asmar}, Zeina and Chollet, {Maria Eugenia} and Ewa Ninio and Audrey Bednarczyk and Dani{\`e}le Thiers{\'e} and Christine Schaeffer and {Van Dorsselaer}, Alain and Christian Boudier and Walter Wahli and Pierre Chambon and Daniel Metzger and Joachim Herz and Philippe Boucher",

note = "Funding Information: We are grateful to J.M. Egly, N. Lemay, M. Mark and N. Ghyselinck (IGBMC, University of Strasbourg) for helpful comments and critical reading of the manuscript, F. Charlotte (Piti{\'e}-Salp{\^e}tri{\`e}re, Paris) for providing us with human artery samples, A. Boos and P. Ronot (University of Strasbourg) for calcium quantifications in aortic samples. P. Lacolley and A. Pizard from INSERM U961, University of Nancy, France for cross-sectional distensibility measurements. E.W. is supported by la Fondation pour la Recherche M{\'e}dicale (FRM). This work was supported by grants from centre national pour la recherche scientifique (CNRS), University of Strasbourg, Fondation de France, Agence Nationale de la Recherche (ANR-06-PHYSIO-032-01 and ANR-09-BLAN-0121-01), the National Institutes of Health, the American Health Assistance Foundation, the Perot Family Foundation, the Consortium for Frontotemporal Dementia Research (CFR) and the Wolfgang-Paul Program of the Humboldt Foundation.",

year = "2012",

doi = "10.1038/ncomms2087",

language = "English (US)",

volume = "3",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - The nuclear hormone receptor PPARγ counteracts vascular calcification by inhibiting Wnt5a signalling in vascular smooth muscle cells

AU - Woldt, Estelle

AU - Terrand, Jérome

AU - Mlih, Mohamed

AU - Matz, Rachel L.

AU - Bruban, Véronique

AU - Coudane, Fanny

AU - Foppolo, Sophie

AU - El Asmar, Zeina

AU - Chollet, Maria Eugenia

AU - Ninio, Ewa

AU - Bednarczyk, Audrey

AU - Thiersé, Danièle

AU - Schaeffer, Christine

AU - Van Dorsselaer, Alain

AU - Boudier, Christian

AU - Wahli, Walter

AU - Chambon, Pierre

AU - Metzger, Daniel

AU - Herz, Joachim

AU - Boucher, Philippe

N1 - Funding Information: We are grateful to J.M. Egly, N. Lemay, M. Mark and N. Ghyselinck (IGBMC, University of Strasbourg) for helpful comments and critical reading of the manuscript, F. Charlotte (Pitié-Salpêtrière, Paris) for providing us with human artery samples, A. Boos and P. Ronot (University of Strasbourg) for calcium quantifications in aortic samples. P. Lacolley and A. Pizard from INSERM U961, University of Nancy, France for cross-sectional distensibility measurements. E.W. is supported by la Fondation pour la Recherche Médicale (FRM). This work was supported by grants from centre national pour la recherche scientifique (CNRS), University of Strasbourg, Fondation de France, Agence Nationale de la Recherche (ANR-06-PHYSIO-032-01 and ANR-09-BLAN-0121-01), the National Institutes of Health, the American Health Assistance Foundation, the Perot Family Foundation, the Consortium for Frontotemporal Dementia Research (CFR) and the Wolfgang-Paul Program of the Humboldt Foundation.

PY - 2012

Y1 - 2012

N2 - Vascular calcification is a hallmark of advanced atherosclerosis. Here we show that deletion of the nuclear receptor PPARγ in vascular smooth muscle cells of low density lipoprotein receptor (LDLr)-deficient mice fed an atherogenic diet high in cholesterol, accelerates vascular calcification with chondrogenic metaplasia within the lesions. Vascular calcification in the absence of PPARγ requires expression of the transmembrane receptor LDLr-related protein-1 in vascular smooth muscle cells. LDLr-related protein-1 promotes a previously unknown Wnt5a-dependent prochondrogenic pathway. We show that PPARγ protects against vascular calcification by inducing the expression of secreted frizzled-related protein-2, which functions as a Wnt5a antagonist. Targeting this signalling pathway may have clinical implications in the context of common complications of atherosclerosis, including coronary artery calcification and valvular sclerosis.

AB - Vascular calcification is a hallmark of advanced atherosclerosis. Here we show that deletion of the nuclear receptor PPARγ in vascular smooth muscle cells of low density lipoprotein receptor (LDLr)-deficient mice fed an atherogenic diet high in cholesterol, accelerates vascular calcification with chondrogenic metaplasia within the lesions. Vascular calcification in the absence of PPARγ requires expression of the transmembrane receptor LDLr-related protein-1 in vascular smooth muscle cells. LDLr-related protein-1 promotes a previously unknown Wnt5a-dependent prochondrogenic pathway. We show that PPARγ protects against vascular calcification by inducing the expression of secreted frizzled-related protein-2, which functions as a Wnt5a antagonist. Targeting this signalling pathway may have clinical implications in the context of common complications of atherosclerosis, including coronary artery calcification and valvular sclerosis.

UR - http://www.scopus.com/inward/record.url?scp=84866975779&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866975779&partnerID=8YFLogxK

U2 - 10.1038/ncomms2087

DO - 10.1038/ncomms2087

M3 - Article

C2 - 23011131

AN - SCOPUS:84866975779

SN - 2041-1723

VL - 3

JO - Nature Communications

JF - Nature Communications

M1 - 1077

ER -

The nuclear hormone receptor PPARγ counteracts vascular calcification by inhibiting Wnt5a signalling in vascular smooth muscle cells

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this