Format

Send to

Choose Destination
Biochim Biophys Acta. 2016 Sep;1861(9 Pt A):1180-1191. doi: 10.1016/j.bbalip.2016.06.017. Epub 2016 Jun 27.

MEK1/2 inhibitors activate macrophage ABCG1 expression and reverse cholesterol transport-An anti-atherogenic function of ERK1/2 inhibition.

Author information

1
Department of Cardiology, Xijing Hospital, the 4th Military Medical University, Xi'an, China.
2
College of Biomedical Engineering, Hefei University of Technology, Hefei, China; School of Medicine, Nankai University, Tianjin, China.
3
College of Life Sciences, Nankai University, Tianjin, China.
4
College of Pharmacy, Nankai University, Tianjin, China.
5
Medical College of Wisconsin, Milwaukee, USA.
6
Weill Cornell Medical College, New York, USA.
7
College of Biomedical Engineering, Hefei University of Technology, Hefei, China; College of Life Sciences, Nankai University, Tianjin, China; State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Biotherapy, Nankai University, Tianjin, China. Electronic address: yduan@hfut.edu.cn.
8
College of Biomedical Engineering, Hefei University of Technology, Hefei, China; College of Life Sciences, Nankai University, Tianjin, China; State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Biotherapy, Nankai University, Tianjin, China. Electronic address: hanjihong2015@hfut.edu.cn.

Abstract

Expression of ATP-binding cassette transporter G1 (ABCG1), a molecule facilitating cholesterol efflux to HDL, is activated by liver X receptor (LXR). In this study, we investigated if inhibition of ERK1/2 can activate macrophage ABCG1 expression and functions. MEK1/2 inhibitors, PD98059 and U0126, increased ABCG1 mRNA and protein expression, and activated the natural ABCG1 promoter but not the promoter with the LXR responsive element (LXRE) deletion. Inhibition of ABCG1 expression by ABCG1 siRNA did enhance the formation of macrophage/foam cells and it attenuated the inhibitory effect of MEK1/2 inhibitors on foam cell formation. MEK1/2 inhibitors activated macrophage cholesterol efflux to HDL in vitro, and they enhanced reverse cholesterol transport (RCT) in vivo. ApoE deficient (apoE(-/-)) mice receiving U0126 treatment had reduced sinus lesions in the aortic root which was associated with activated macrophage ABCG1 expression in the lesion areas. MEK1/2 inhibitors coordinated the RXR agonist, but not the LXR agonist, to induce ABCG1 expression. Furthermore, induction of ABCG1 expression by MEK1/2 inhibitors was associated with activation of SIRT1, a positive regulator of LXR activity, and inactivation of SULT2B1 and RIP140, two negative regulators of LXR activity. Taken together, our study suggests that MEK1/2 inhibitors activate macrophage ABCG1 expression/RCT, and inhibit foam cell formation and lesion development by multiple mechanisms, supporting the concept that ERK1/2 inhibition is anti-atherogenic.

KEYWORDS:

ABCG1; Atherosclerosis; LXR; MEK1/2; RCT; SIRT1

PMID:
27365310
DOI:
10.1016/j.bbalip.2016.06.017
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center