| First Author | Hwang HJ | Year | 2017 |
| Journal | Biochim Biophys Acta | Volume | 1863 |
| Issue | 6 | Pages | 1436-1444 |
| PubMed ID | 28215577 | Mgi Jnum | J:255460 |
| Mgi Id | MGI:6105399 | Doi | 10.1016/j.bbadis.2017.02.018 |
| Citation | Hwang HJ, et al. (2017) Knockdown of sestrin2 increases pro-inflammatory reactions and ER stress in the endothelium via an AMPK dependent mechanism. Biochim Biophys Acta 1863(6):1436-1444 |
| abstractText | 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-kappaB) 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-kappaB 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. |
