Growth Differentiation Factor-15 Deficiency Inhibits Atherosclerosis Progression by Regulating Interleukin-6-Dependent Inflammatory Response to Vascular Injury

Background-Growth differentiation factor (GDF)-15 is a distant and divergent member of the transforming growth factor-beta superfamily (TGF-beta). 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. Methods and 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.