title: Growth differentiation factor-15 deficiency inhibits atherosclerosis progression by regulating interleukin-6-dependent inflammatory response to vascular injury.
abstract: BACKGROUND
  Growth differentiation factor (GDF)-15 is a distant and divergent member of the transforming growth factor-β superfamily (TGF-β) . There is growing evidence indicating the involvement of GDF-15 in various pathologies. Expression of GDF-15 is induced under conditions of inflammation and increased GDF-15 serum levels are suggested as a risk factor for cardiovascular diseases.
  
  
  RESULTS
  We show here that GDF-15 and proinflammatory cytokine interleukin (IL)-6 levels are highly increased (5-fold) in cultured oxidized low-density lipoproteins-stimulated peritoneal macrophages derived from GDF-15(+/+)/apolipoprotein (apo) E(-/-), mice. Notably, IL-6 induction on oxidized low-density lipoproteins stimulation is completely abolished in the absence of GDF-15. Consistent with our in vitro data GDF-15 mRNA expression and protein levels are upregulated (2.5- to 6-fold) in the atherosclerotic vessel wall of GDF-15(+/+)/apoE(-/-) mice after a cholesterol-enriched diet. GDF-15 deficiency inhibits lumen stenosis (52%) and (18)FDG uptake (34%) in the aortic arch despite increased serum triglyceride/cholesterol levels and elevated body weight. Immunohistomorphometric investigations of atherosclerotic lesions reveal a decreased percentage of inflammatory CD11b(+) (57%) or IL-6(+), leukocytes, and apoptotic cells (74%) after 20 weeks. However, the total number of macrophages and cell density in atherosclerotic lesions of the innominate artery are increased in GDF-15(-/-)/apoE(-/-) mice.
  
  
  CONCLUSIONS
  Our data suggest that GDF-15 is involved in orchestrating atherosclerotic lesion progression by regulating apoptotic cell death and IL-6-dependent inflammatory responses to vascular injury.
authors: Institute of Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, Marburg, Germany.
authors: Gabriel A
authors: GA
authors: Bonaterra
authors: Stefanie
authors: S
authors: Zügel
authors: Joel
authors: J
authors: Thogersen
authors: Sabrina A
authors: SA
authors: Walter
authors: Uwe
authors: U
authors: Haberkorn
authors: Jens
authors: J
authors: Strelau
authors: Ralf
authors: R
authors: Kinscherf
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology*; D001835:Body Weight; D016122:Brachiocephalic Trunk / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D018450:Disease Progression; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007249:Inflammation / Q000503:physiopathology*; D015850:Interleukin-6 / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D049268:Positron-Emission Tomography; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation
chemical_list: D055436:Growth Differentiation Factor 15; D015850:Interleukin-6; D012333:RNA, Messenger; D014280:Triglycerides; D002784:Cholesterol
keywords: GDF‐15; atherosclerosis; inflammation; interleukins