Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis.
Growth differentiation factor (GDF) 15 is a member of the transforming growth factor β (TGF-β) superfamily, which operates in acute phase responses through a currently unknown receptor. Elevated GDF-15 serum levels were recently identified as a risk factor for acute coronary syndromes. We show that GDF-15 expression is up-regulated as disease progresses in murine atherosclerosis and primarily colocalizes with plaque macrophages. Hematopoietic GDF-15 deficiency in low density lipoprotein receptor(-/-) mice led to impaired initial lesion formation and increased collagen in later lesions. Although lesion burden in GDF-15(-/-) chimeras was unaltered, plaques had reduced macrophage infiltrates and decreased necrotic core formation, all features of improved plaque stability. In vitro studies pointed to a TGFβRII-dependent regulatory role of GDF-15 in cell death regulation. Importantly, GDF-15(-/-) macrophages displayed reduced CCR2 expression, whereas GDF-15 promoted macrophage chemotaxis in a strictly CCR2- and TGFβRII-dependent manner, a phenomenon which was not observed in G protein-coupled receptor kinase 2(+/-) macrophages. In conclusion, GDF-15 deletion has a beneficial effect both in early and later atherosclerosis by inhibition of CCR2-mediated chemotaxis and by modulating cell death. Our study is the first to identify GDF-15 as an acute phase modifier of CCR2/TGFβRII-dependent inflammatory responses to vascular injury.
Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, Netherlands. s.de.jager@lacdr.leidenuniv.nl
Saskia C A
SC
de Jager
Beatriz
B
Bermúdez
Ilze
I
Bot
Rory R
RR
Koenen
Martine
M
Bot
Annemieke
A
Kavelaars
Vivian
V
de Waard
Cobi J
CJ
Heijnen
Francisco J G
FJ
Muriana
Christian
C
Weber
Theo J C
TJ
van Berkel
Johan
J
Kuiper
Se-Jin
SJ
Lee
Rocio
R
Abia
Erik A L
EA
Biessen
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D050197:Atherosclerosis / Q000517:prevention & control*; D016026:Bone Marrow Transplantation; D002633:Chemotaxis / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000502:physiology*; D055436:Growth Differentiation Factor 15 / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D007150:Immunohistochemistry; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis / Q000502:physiology; D054390:Receptors, CCR2 / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
C515335:Ccr2 protein, mouse; D017931:DNA Primers; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; D054390:Receptors, CCR2; D011973:Receptors, LDL
Cell Tissue Res. 2004 Nov;318(2):325-33
15459768
Arthritis Rheum. 2008 Jul;58(7):1931-9
18576354
Arthritis Rheum. 2007 Mar;56(3):753-64
17328047
J Leukoc Biol. 2006 Dec;80(6):1214-21
16943386
Arterioscler Thromb Vasc Biol. 2005 May;25(5):1014-9
15774908
Eur Heart J. 2008 Dec;29(23):2947; author reply 2947-8
18927212
Arterioscler Thromb Vasc Biol. 2008 Aug;28(8):1421-8
18451332
Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2985-90
9501202
Nat Rev Neurosci. 2005 Dec;6(12):945-54
16340955
Arterioscler Thromb Vasc Biol. 2002 Jun 1;22(6):975-82
12067907
Eur Heart J. 2009 May;30(9):1057-65
19168526
Cell. 2003 Jun 13;113(6):685-700
12809600
Circ Res. 2006 Feb 17;98(3):342-50
16397142
Arterioscler Thromb Vasc Biol. 2008 Aug;28(8):1429-31
18467644
Circulation. 2007 Feb 27;115(8):962-71
17283261
Curr Opin Genet Dev. 1996 Aug;6(4):432-8
8791534
Arterioscler Thromb Vasc Biol. 2003 Mar 1;23(3):447-53
12615695
EMBO J. 2005 Sep 21;24(18):3247-58
16121194
Circ Res. 2006 Feb 17;98(3):351-60
16397141
Eur Heart J. 2008 Oct;29(19):2327-35
18664460
Genes Dev. 1994 Jan;8(2):133-46
8299934
Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11514-9
9326641
J Clin Invest. 2007 Jan;117(1):185-94
17200718
Annu Rev Biochem. 1998;67:753-91
9759503
Circ Res. 1999 Nov 12;85(10):931-9
10559140
Mol Cell Biol. 2000 May;20(10):3742-51
10779363
Circ Res. 2001 Nov 9;89(10):930-4
11701621
Cell. 2000 Oct 13;103(2):295-309
11057902