Growth differentiation factor (GDF) 15 is a member of the transforming growth factor(TGF-) 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 TGF RII-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 TGF RII-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/TGF RII-dependent inflammatory responses to vascular injury.

© 2011 de Jager et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www. rupress. org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons. org/licenses/by-nc-sa/3.0/).