gms | German Medical Science

24. Jahrestagung der Deutschen Gesellschaft für Arterioskleroseforschung

Deutsche Gesellschaft für Arterioskleroseforschung

18.03. - 20.03.2010, Blaubeuren

Role of GDF-15 (growth differentiation factor 15) in the progression of atherosclerosis in apoE deficient mice

Meeting Contribution

  • corresponding author S. Zügel - Anatomy and Cell Biology, Philipps-University Marburg, Germany
  • G. A. Bonaterra - Anatomy and Cell Biology, Philipps-University Marburg, Germany
  • S. Vorwald - Anatomy and Cell Biology III, Ruprecht-Karls-University Heidelberg, Germany
  • G. Bendner - Anatomy and Cell Biology III, Ruprecht-Karls-University Heidelberg, Germany
  • J. Strelau - Anatomy and Cell Biology III, Ruprecht-Karls-University Heidelberg, Germany
  • R. Kinscherf - Anatomy and Cell Biology, Philipps-University Marburg, Germany

Deutsche Gesellschaft für Arterioskleroseforschung e.V.. 24. Jahrestagung der Deutschen Gesellschaft für Arterioskleroseforschung. Blaubeuren, 18.-20.03.2010. Düsseldorf: German Medical Science GMS Publishing House; 2011. Doc10dgaf12

doi: 10.3205/10dgaf12, urn:nbn:de:0183-10dgaf120

Published: March 23, 2011

© 2011 Zügel et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.


Growth differentiation factor-15 (GDF-15) is a member of the TGF-β superfamily as well as an important regulator of proliferation, differentiation and inflammatory processes and is found in macrophages of human atherosclerotic plaque. Hence the goal of the study was to investigate the effect of GDF-15 in the development and progression of atherosclerosis in apoE deficient (apoE-/-) mice.


Growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1), is a member of the transforming growth factor (TGF-β) superfamily. TGF-βs are cytokines that exert prominent functions in tissue homeostasis and adaptation by regulating cell survival, proliferation, differentiation and inflammatory processes. It has been shown that GDF-15 is involved in the regulation of proapoptotic/antiinflammatory processes under contribution of p53 and poly-ADP-polymerase (PARP), interleukin-1 (IL-1), cyclooxygenase-1/2 (COX-1, COX-2) or tumor necrosis factor-α (TNF-α) [1], [2], [3], [4], [5], [6]. Additionally, oxidized low density lipoproteins (oxLDL), which are involved in the development of atherosclerosis, induce the expression of GDF-15 in human macrophages with a simultaneous increase of the apoptosis rate [7]. Moreover, it has recently been shown that GDF-15 and oxLDL are colocalized in human macrophages of atherosclerotic lesions [7]. Thus, the aim of our study was to investigate the effect of GDF-15 in the development and progression of atherosclerosis in apoE deficient (apoE-/-) mice.


ApoE-/-/GDF-15+/+ and apoE-/-/GDF-15-/- mice were generated by cross-breeding of apoE-/- and GDF-15 LacZ-knockin mice. At an age of 10 weeks, the offspring were fed with a high cholesterol diet (western diet) for a period of 12 weeks. Thereafter, the innominate artery (=brachiocephalic trunk) was removed, shock-frozen in liquid nitrogen-cooled isopentane and 6 µm cryo-sections were generated. The extent of atherosclerotic plaques was measured by computer-assisted morphometry (Figure 1 [Fig. 1]). Detection of BM8 and MOMA-2 (macrophages), Ki67 (proliferation), COX-2 and MIF (inflammation) was quantified via immunohistological staining including computer-assisted morphometry.


In apoE-/-/GDF-15-/- mice we found an inhibition of lumen stenosis of 17% (p=0.05) compared to apoE-/-/GDF-15+/+ mice (Figure 2 [Fig. 2]). Furthermore, the density (cells/mm²) of COX-2 (+91%, p=0.02; Figure 3 [Fig. 3]) and MIF (+202%, p=0.04; Figure 4 [Fig. 4]) positive cells was increased in atherosclerotic lesions of apoE-/-/GDF-15-/- mice compared to apoE-/-/GDF-15+/+ mice. Additionally, in atherosclerotic lesions of apoE-/-/GDF-15-/- the density of Ki67 positive cells was significantly increased (+94%, p=0.05), whereas the percentage of BM8 and MOMA-2 positive cells was similar in atherosclerotic lesions of both groups under test (not shown).


Previous data have shown that GDF-15 immunoreactivity is localized in macrophages of human atherosclerotic lesions [7]. Thus, it could be hypothesized that GDF-15 plays a role during development and progression of atherosclerosis. Indeed, we show here that GDF-15 deficiency significantly inhibits the progression of atherosclerotic plaques in the innominate artery of cholesterol-fed apoE-/- mice. Furthermore, atherosclerosis is an inflammatory disease [8] and proinflammatory as well as proapoptotic cytokines have been shown to be co-localized in cells of human atherosclerotic lesions [9], [10]. According to previous data in humans, we found in atherosclerotic plaques of apoE-/- mice MIF and COX-2 immunoreactive cells. Because GDF-15 deficiency increased the expression of MIF and COX-2, it is tempting to speculate that GDF-15 is involved in expression of these pro-inflammatory cytokines. Moreover, an increased density of MIF and COX-2 expressing cells seems to result in an enhanced pro-inflammatory status of the plaque area. MIF has been shown to be produced by macrophages in all types of atherosclerotic lesions, where it has been suggested to play a significant role by maintaining the activation-mediated induction of inflammatory processes [10], [11] and to play a role in the destabilization of human atherosclerotic plaque [12]. However, we found that lumen stenosis is reduced in apoE-/-/GDF-15-/- mice, which may indicate that GDF-15 is associated with plaque stability/instability status. In macrophages of human atherosclerotic lesions a co-localization of GDF-15 with oxLDL as well as with inflammatory and/or apoptotic markers were likewise found [7], so that it can be hypothesized that GDF-15 is an early mediator of damage, which could adjust inflammation [9] survival, proliferation or apoptosis during illness processes [13]. Finally, according to our results, we assume that GDF-15 supports the progression of atherosclerosis, however independent from induction of inflammatory reactions and proliferative processes.


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