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

Ling Zhang1, Yuanli Chen2, Xiaoxiao Yang3

  • 1Department of Cardiology, Xijing Hospital, the 4th Military Medical University, Xi'an, China.

Biochimica Et Biophysica Acta
|July 2, 2016
PubMed

Insights

Inhibiting ERK1/2 with MEK1/2 inhibitors boosts macrophage ABCG1 expression and cholesterol efflux, reducing foam cell formation and atherosclerosis. This suggests ERK1/2 inhibition is a promising anti-atherogenic strategy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Research

Background:

  • ATP-binding cassette transporter G1 (ABCG1) facilitates cholesterol efflux to HDL and is activated by liver X receptor (LXR).
  • The role of ERK1/2 signaling in regulating ABCG1 expression and macrophage function in atherosclerosis is not fully understood.

Purpose of the Study:

  • To investigate whether inhibition of extracellular signal-regulated kinases 1/2 (ERK1/2) can activate macrophage ABCG1 expression and its associated functions.
  • To explore the mechanisms by which MEK1/2 inhibitors influence ABCG1 expression and cholesterol homeostasis.
  • To assess the anti-atherogenic potential of ERK1/2 inhibition in vivo.

Main Methods:

  • Utilized MEK1/2 inhibitors (PD98059, U0126) to study ABCG1 expression and promoter activity in macrophages.
  • Employed ABCG1 siRNA to assess the role of ABCG1 in foam cell formation and the effects of MEK1/2 inhibitors.
  • Evaluated cholesterol efflux to HDL in vitro and reverse cholesterol transport (RCT) in vivo.
  • Administered U0126 to ApoE deficient mice to assess lesion development in the aortic root.
  • Investigated the interaction of MEK1/2 inhibitors with RXR and LXR agonists and their effects on regulatory proteins (SIRT1, SULT2B1, RIP140).

Main Results:

  • MEK1/2 inhibitors significantly increased ABCG1 mRNA and protein expression and activated the natural ABCG1 promoter.
  • Inhibition of ABCG1 expression enhanced foam cell formation, while MEK1/2 inhibitors attenuated this effect.
  • MEK1/2 inhibitors promoted cholesterol efflux to HDL in vitro and enhanced RCT in vivo.
  • U0126 treatment in ApoE(-/-) mice reduced aortic root lesions, correlating with increased macrophage ABCG1 expression.
  • MEK1/2 inhibitors induced ABCG1 expression via coordination with RXR agonists and modulation of SIRT1, SULT2B1, and RIP140, independent of direct LXR activation.

Conclusions:

  • MEK1/2 inhibitors activate macrophage ABCG1 expression and function through multiple mechanisms, including modulation of regulatory proteins.
  • ERK1/2 inhibition promotes cholesterol efflux and reverse cholesterol transport, inhibiting foam cell formation and lesion development.
  • These findings support the concept that ERK1/2 inhibition possesses anti-atherogenic properties.
Keywords:
ABCG1AtherosclerosisLXRMEK1/2RCTSIRT1

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