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Sci Rep. 2015 Nov 25;5:17194. doi: 10.1038/srep17194.

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

Ma X1,2,3, Qiu R1,2, Dang J1,2,4, Li J1,2, Hu Q5, Shan S1,2, Xin Q1,2, Pan W6, Bian X1,2, Yuan Q1,2, Long F1,2, Liu N1,2, Li Y1,2, Gao F1,2, Zou C3, Gong Y1,2, Liu Q1,2.

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The Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.
Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China.
Department of Cardiac Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
Department of Medical Genetics and Cell Biology, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China.
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China.
Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China.


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.

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