Growth differentiation factor-15 regulates oxLDL-induced lipid homeostasis and autophagy in human macrophages.
ATG5
Autophagy
GDF-15
oxLDL
p62
Journal
Atherosclerosis
ISSN: 1879-1484
Titre abrégé: Atherosclerosis
Pays: Ireland
ID NLM: 0242543
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
06
07
2018
revised:
06
12
2018
accepted:
07
12
2018
pubmed:
19
1
2019
medline:
14
4
2020
entrez:
19
1
2019
Statut:
ppublish
Résumé
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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 30658188
pii: S0021-9150(18)31540-5
doi: 10.1016/j.atherosclerosis.2018.12.009
pii:
doi:
Substances chimiques
Autophagy-Related Proteins
0
GDF15 protein, human
0
Growth Differentiation Factor 15
0
Lipoproteins, LDL
0
Recombinant Proteins
0
oxidized low density lipoprotein
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
128-136Informations de copyright
Copyright © 2018 Elsevier B.V. All rights reserved.