Knockdown of sestrin2 increases pro-inflammatory reactions and ER stress in the endothelium via an AMPK dependent mechanism

Hwan Jin Hwang, Tae Woo Jung, Ju Hee Choi, Hyun Jung Lee, Hye Soo Chung, Ji A. Seo, Sin Gon Kim, Nan Hee Kim, Kyung Mook Choi, Dong Seop Choi, Sei Hyun Baik, Hye Jin Yoo

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

Background & Objective Sestrin2 (sesn2) has recently gained attention as an important regulator for various metabolic disorders. Sesn2 is involved in AMP-activated protein kinase (AMPK) activation, which leads to anti-inflammatory and anti-oxidative responses. However, the role of sesn2 in the endothelium has not yet been clarified. Methods To evaluate sesn2-mediated anti-atherosclerotic effects, siRNA to silence sesn2 expression was introduced to human umbilical vein endothelial cells (HUVECs), THP-1 cells and C57BL/6 mice. Lipopolysaccharide (LPS) was administrated to sesn2-knockdown cells and mice to induce atherosclerotic signals. Results Knockdown of sesn2 was involved with atherosclerotic reactions caused by LPS treatment through decrease of AMPK phosphorylation. In sesn2-knockdown HUVECs and THP-1 cells, LPS-mediated nuclear factor kappa B (NF-κB) phosphorylation and secretion of pro-inflammatory cytokines were both significantly increased. In HUVECs, expression of adhesion molecules and LPS-stimulated adhesion of THP-1 cells to the endothelium were significantly increased after sesn2-knockdown. Furthermore, LPS-induced reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, and cell toxicity were all significantly elevated after sesn2-knockdown in HUVECs. Interestingly, all these pro-atherosclerotic effects were fully abrogated by treatment with an AMPK activator. In aortic tissue samples from C57BL/6 mice, sesn2-knockdown using siRNA oligomers resulted in reduced AMPK phosphorylation and induction of LPS-mediated NF-κB phosphorylation, leading to up-regulation of adhesion molecules and ER stress-related signaling. Conclusion Knockdown of sesn2 aggravates atherosclerotic processes by increasing pro-inflammatory reactions and ER stress in the endothelium via an AMPK-dependent mechanism, suggesting that sesn2 might be a novel therapeutic target for atherosclerosis.

Original languageEnglish
Pages (from-to)1436-1444
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1863
Issue number6
DOIs
Publication statusPublished - 2017 Jun 1

Keywords

  • AMPK
  • Atherosclerosis
  • ER stress
  • Endothelium
  • Pro-inflammatory reactions
  • Sesn2

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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