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ALK7 Acts as a Positive Regulator of Macrophage Activation through Down-Regulation of PPARγ Expression.

Authors :
Cheng WL
Zhang Q
Cao JL
Chen XL
Li W
Zhang L
Chao SP
Zhao F
Source :
Journal of atherosclerosis and thrombosis [J Atheroscler Thromb] 2021 Apr 01; Vol. 28 (4), pp. 375-384. Date of Electronic Publication: 2020 Jul 09.
Publication Year :
2021

Abstract

Aim: Activin receptor-like kinase 7 (ALK7) acts as a key receptor for TGF-β family members, which play important roles in regulating cardiovascular activity. However, ALK7's potential role, and underlying mechanism, in the macrophage activation involved in atherogenesis remain unexplored.<br />Methods: ALK7 expression in macrophages was tested by RT-PCR, western blot, and immunofluorescence co-staining. The loss-of-function strategy using AdshALK7 was performed for functional study. Oil Red O staining was used to observe the foam cell formation, while inflammatory mediators and genes related to cholesterol efflux and influx were determined by RT-PCR and western blot. A PPARγ inhibitor (G3335) was used to reveal whether PPARγ was required for ALK7 to affect macrophage activation.<br />Results: The results exhibited upregulated ALK7 expression in oxidized low-density lipoprotein (Ox-LDL) induced bone marrow derived macrophages (BMDMs) and mouse peritoneal macrophages (MPMs), isolated from ApoE-deficient mice, while ALK7's strong immunoreactivity in BMDMs was observed. ALK7 knockdown significantly attenuated pro-inflammatory, but promoted anti-inflammatory, macrophage markers expression. Additionally, ALK7 silencing decreased foam cell formation, accompanied by the up-regulation of ABCA1 and ABCG1 involved in cholesterol efflux but the down-regulation of CD36 and SR-A implicated in cholesterol influx. Mechanistically, ALK7 knockdown upregulated PPARγ expression, which was required for the ameliorated effect of ALK7 silencing macrophage activation.<br />Conclusions: Our study demonstrated that ALK7 was a positive regulator for macrophage activation, partially through down-regulation of PPARγ expression, which suggested that neutralizing ALK7 might be promising therapeutic strategy for treating atherosclerosis.

Details

Language :
English
ISSN :
1880-3873
Volume :
28
Issue :
4
Database :
MEDLINE
Journal :
Journal of atherosclerosis and thrombosis
Publication Type :
Academic Journal
Accession number :
32641645
Full Text :
https://doi.org/10.5551/jat.54445