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The feedback loop of "EMMPRIN/NF-κB" worsens atherosclerotic plaque via suppressing autophagy in macrophage.

Abstract：

:This study examined the significance of macrophage autophagy in extracellular matrix metalloproteinase inducer (EMMPRIN)-mediated atherosclerosis (AS). Apolipoprotein E-deficient (ApoE-/-) mice were fed a western diet to establish an AS model. EMMPRIN and p62/Sequestosome-1(SQSTM1) expression were evaluated in plaque macrophages from the AS mice using immunofluorescence. The EMMPRIN and p62/SQSTM1 protein expression levels in macrophages increased with the increasing vulnerability of the atherosclerotic plaques. RAW264.7 cells and ApoE-/- mice Bone Marrow-derived macrophages were transfected with different small interfering RNAs (siRNAs) or plasmids, or treated with different drugs in the presence or absence of oxidized low-density lipoprotein (oxLDL). The protein levels of the targets were evaluated using western blotting (WB), and the autophagosomes were observed under a transmission electron microscope (TEM). Over-expressed EMMPRIN dramatically inhibited oxLDL-mediated autophagy. EMMPRIN also negatively regulated autophagy primarily through the nuclear factor-kappa B (NF-κB) signalling pathway. In turn, activated NF-κB up-regulated EMMPRIN expression. Inhibition of EMMPRIN decreased cell apoptosis and the release of inflammatory cytokines via the promotion of macrophage autophagy. Infection with an adenovirus delivering the EMMPRIN-siRNA ameliorated AS, promoted macrophage autophagy in plaques and reduced the serum TNF-α, IL-6, MCP-1 and NF-κB expression levels in the AS mice. Chloroquine (CQ) reversed these effects. This study revealed for the first time that the feedback loop of the "EMMPRIN/NF-κB" pathway plays an important role in atherosclerotic plaques via modulation of autophagy in macrophages, which might provide a potential strategy for the clinical treatment of AS.

journal_name

J Mol Cell Cardiol

journal_title

Journal of molecular and cellular cardiology

authors

Liang X,Hou X,Yang Y,Liu H,Guo R,Yang Z,Yang L

doi

10.1016/j.yjmcc.2017.11.008

subject

Has Abstract

pub_date

2018-01-01 00:00:00

pages

129-140

eissn

0022-2828

issn

1095-8584

pii

S0022-2828(17)30343-7

journal_volume

114

pub_type

杂志文章

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The feedback loop of "EMMPRIN/NF-κB" worsens atherosclerotic plaque via suppressing autophagy in macrophage.