Growth differentiation factor-15 regulates oxLDL-induced lipid homeostasis and autophagy in human macrophages

Background and aims: Growth differentiation factor-15 (GDF-15)/macrophage inhibitory cytokine-1 (MIC-1/GDF15) is associated with cardiovascular disease, inflammation and development of atherosclerosis and is highly expressed in macrophages (M Phi) of atherosclerotic lesions. Thus, we were interested in investigating the influence of GDF-15 in lipid homeostasis and autophagy in human MF during foam cell formation. Methods and results: Oxidized-low density lipoprotein (50 mu g/ml oxLDL), recombinant (r)GDF-15, transiently silenced GDF-15 (siGDF-15 M Phi), as well as with negative siRNA transfected (nsiGDF-15 M Phi) PMA-differentiated human THP-1 M Phi, were used to investigate the effects of GDF-15 on autophagic processes and lipid accumulation. Oil Red O staining revealed that rGDF-15 alone, but also in combination with oxLDL, significantly increased the lipid accumulation in THP-1 M Phi; a reverse effect was detected in siGDF-15 M Phi. Western-blot analyses and confocal laser scanning microscopy showed an increase of Atg5, Atg12/Atg5 protein complex and p62 protein in THP-1 M Phi co-incubated with rGDF-15 and oxLDL, as well as an increase of p62 accumulation compared to rGDF-15-treated MF. Vice versa, siGDF-15 M Phi showed a reduced p62 accumulation compared to nsiGDF-15 M Phi. The present study indicates that GDF-15, especially in combination with oxLDL, regulates the expression of autophagy-relevant proteins (p62, Atg5 and Atg12/Atg5 protein complex) and p62 accumulation in human M Phi. Conclusions: GDF-15, in combination with oxLDL, impairs autophagic processes with consequences for lipid homeostasis in human M Phi, indicating its novel important pathophysiological role in atherosclerotic plaque development and progression.