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.

ORMDL proteins regulate ceramide levels during sterile inflammation

“…Numerous genome-wide association studies have linked ORMDL3 SNPs to increased risk of asthma development (32,33), while others have linked them to inflammatory disorders, including colitis, diabetes, and atherosclerosis (34,35). Therefore, we examined whether ORMDL expression is modulated physiologically during inflammatory responses.…”

A variant in SMOC2, inhibiting BMP signaling by competitively binding to BMPR1B, causes multiple epiphyseal dysplasia

“…Recombinant lentiviruses and stably transfected cell line were established as described in previous study [ 37 ] . Stably transfected cells were seeded in a 100-mm 2 dish at 80% density.…”

ORMDL3 and its implication in inflammatory disorders

“…However, it is still not fully clear through which vital signal pathways or via which crucial molecules ORMDL3 modulates autophagy. Further, knockdown of ORMDL3 promotes ox‐LDL‐induced apoptosis in ECs, implying that ORMDL3 might represent a protective mechanism against environmental threats via regulation of autophagy . Our group have very recently illuminated that ORMDL3 facilitated the survival of splenic B cells via an ATF6 (activating transcription factor 6)‐ERS‐Beclin1‐autophagy regulatory pathway in the context of systemic lupus erythematosus.…”

“…In 2012, Kurreeman and his group applied a multi‐ethnic approach to identify rheumatoid arthritis (RA) susceptibility loci and identified IKZF3‐ORMDL3‐GSDMB at the 17q12 locus most likely associated with RA . Our group has recently shown the association of ORMDL3 variants with atherosclerosis in a Chinese Han population . We first presented the evidence of two SNPs regulating ORMDL3 expression (rs7216389 and rs9303277) significantly associated with AS risk and the evidence of increased ORMDL3 expression in atherosclerosis cases compared to controls.…”

“…Since the initial identification of its genetic association with bronchial asthma (hereafter referred to as asthma), the ORMDL3 gene ( ORMDL Sphingolipid Biosynthesis Regulator 3 ) has been intensely investigated for its particular involvement in common inflammatory disorders. Efforts of more than one decade have pointed to the genetic polymorphisms within 17q21 that harbors the ORMDL3 gene, toward several well‐documented inflammatory diseases, such as asthma, inflammatory bowel disease (IBD), ankylosing spondylitis and atherosclerosis . Subsequent studies on gene function have gained increasing attention for its role in endoplasmic reticulum stress (ERS), ceramide metabolism, inflammatory reactions and most recently, autophagy, apoptosis and B lymphocyte fate determination .…”