Growth differentiation factor-15 regulates oxLDL-induced lipid homeostasis and autophagy in human macrophages. (February 2019)

• Record Type: Journal Article
• Authors: Ackermann, Kathrin; Bonaterra, Gabriel A.; Kinscherf, Ralf; Schwarz, Anja
• Is Part Of: Atherosclerosis. Volume 281(2019)
• Page Start: 128
• Page End: 136
• Publication Date: 2019-02
• Subjects: Autophagy -- p62 -- ATG5 -- GDF-15 -- oxLDL; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2018.12.009
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: 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 (MΦ) of atherosclerotic lesions. Thus, we were interested in investigating the influence of GDF-15 in lipid homeostasis and autophagy in human MΦ during foam cell formation. Methods and results: Oxidized-low density lipoprotein (50 μg/ml oxLDL), recombinant (r)GDF-15, transiently silenced GDF-15 ( siGDF-15 MΦ ), as well as with negative siRNA transfected ( nsiGDF-15 MΦ ) PMA-differentiated human THP-1 MΦ, 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 MΦ ; a reverse effect was detected in siGDF-15 MΦ . Western-blot analyses and confocal laser scanning microscopy showed an increase of Atg5, Atg12/Atg5 protein complex and p62 protein in THP-1 MΦ co-incubated with rGDF-15 and oxLDL, as well as an increase of p62 accumulation compared to rGDF-15-treated MΦ. Vice versa, siGDF-15 MΦ showed a reduced p62 accumulation compared to nsiGDF-15 MΦ . 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 MΦ. Conclusions: GDF-15, in combination with oxLDL, impairs autophagic processes with consequences for lipid homeostasis in human MΦ, indicating its novel important pathophysiological role in atherosclerotic plaque development and progression. Graphical abstract: Image 1 Highlights: GDF-15 enhances oxLDL-independent lipid-accumulation in human MΦ. GDF-15 silencing in human MΦ inhibits oxLDL-induced lipid-accumulation. Incubation of human MΦ with rGDF-15/oxLDL increases ATG5, ATG12/ATG5-complex and p62. GDF-15 silencing in human MΦ reduces ATG5, ATG12/ATG5-complex and p62. GDF-15/oxLDL impairs autophagy with consequences for lipid homeostasis in human MΦ.