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. 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 ^+/+ /apo E ^−/− 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 CD 11b ⁺ (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 ^−/− /apo E ^−/− 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.