ORMDL3 contributes to the risk of atherosclerosis in Chinese Han population and mediates oxidized low-density lipoprotein-induced autophagy in endothelial cells.

Abstract

ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) is a universally confirmed susceptibility gene for asthma and has recently emerged as a crucial modulator in lipid metabolism, inflammation and endoplasmic reticulum (ER) stress-the mechanisms also closely involved in atherosclerosis (AS). Here we first presented the evidence of two single nucleotide polymorphisms regulating ORMDL3 expression (rs7216389 and rs9303277) significantly associated with AS risk and the evidence of increased ORMDL3 expression in AS cases compared to controls, in Chinese Han population. Following the detection of its statistical correlation with AS, we further explored the functional relevance of ORMDL3 and hypothesized a potential role mediating autophagy as autophagy is activated upon modified lipid, inflammation and ER stress. Our results demonstrated that in endothelial cells oxidized low-density lipoprotein (ox-LDL) up-regulated ORMDL3 expression and knockdown of ORMDL3 alleviated not only ox-LDL-induced but also basal autophagy. BECN1 is essential for autophagy initiation and silencing of ORMDL3 suppressed ox-LDL-induced as well as basal BECN1 expression. In addition, deletion of ORMDL3 resulted in greater sensitivity to ox-LDL-induced cell death. Taken together, ORMDL3 might represent a causal gene mediating autophagy in endothelial cells in the pathogenesis of AS.

• Authors: Xiaochun Ma, Rongfang Qiu, Jie Dang, Jiangxia Li, Qin Hu, Shan Shan, Qian Xin, Wenying Pan, Xianli Bian, Qianqian Yuan, Feng Long, Na Liu, Yan Li, Fei Gao, Chengwei Zou, Yaoqin Gong, Qiji Liu
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 17194 (Nov 25 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26603569 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• Lipoproteins, LDL
• Membrane Proteins
• ORMDL3 protein, human
• oxidized low density lipoprotein

Topics

• Aged
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Asian People (genetics)
• Atherosclerosis (genetics, metabolism, pathology)
• Autophagy (drug effects)
• Beclin-1
• Case-Control Studies
• China
• Cohort Studies
• Endoplasmic Reticulum Stress
• Female
• Genotype
• Human Umbilical Vein Endothelial Cells
• Humans
• Lipoproteins, LDL (toxicity)
• Male
• Membrane Proteins (antagonists & inhibitors, genetics, metabolism)
• Middle Aged
• RNA Interference
• Risk Factors
• Up-Regulation (drug effects)