Abstract 16725: A Novel Role for MAGI1 in Disturbed Flow-Induced Endoplasmic Reticulum Stress in Endothelial Cells

• Published in: Circulation (New York, N.Y.) N.Y.), 2018-11, Vol.138 (Suppl_1 Suppl 1), p.A16725-A16725
• Main Authors: Paez-Mayorga, Jesus, Wang, Yin, Kotla, Sivareddy, Abe, Junichi, Le, Nhat-Tu
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.138.suppl_1.16725

IntroductionAtherosclerotic plaque predominantly develops in areas where endothelial cells (ECs) are exposed to disturbed flow (d-flow). Endoplasmic reticulum (ER) stress, characterized by the activation of ER transmembrane sensor ATF6 and transcription factor XBP-1, has been implicated in d-flow-induced atherogenesis. At d-flow regions, expression of both total and spliced XBP-1 and activation of ATF6 are increased, resulting in EC apoptosis. Additionally, over-expression of XBP-1 accelerates atherosclerotic formation. A recent genome-wide association study revealed a strong correlation between membrane-associated guanylate kinase with inverted domain structure-1 (MAGI1), a scaffold protein that associates with the tight and adherens junctions, and chronic inflammatory diseases.HypothesisWe hypothesize that MAGI1 is crucial in d-flow-induced EC inflammation, apoptosis, and atherogenesis via regulating ER stress signaling.Methods and ResultsMicroarray analysis revealed that MAGI1 depletion inhibits ER-stress related genes, including XBP-1. qRT-PCR results confirmed that MAGI1 depletion abolished d-flow-mediated expression of spliced and full-length XBP-1 which correlated with reduced d-flow-induced apoptosis. To examine the mechanism by which MAGI1 regulates ER stress signaling, we found that MAGI1 is associated with ATF6, and that MAGI1-ATF6 complex formation is increased by inflammatory stimuli including d-flow and thrombin. Because the cleaved form of ATF6 can translocate from ER and Golgi to the nucleus, where it binds to ER-stress response elements and upregulates XBP-1 expression, we asked if MAGI1 facilitates ATF6 nuclear translocation. We found that thrombin-mediated ATF6 nuclear translation is significantly inhibited by MAGI1 depletion.ConclusionsOur results indicate that d-flow elicits the formation and translocation of a MAGI1-ATF6 complex from the cytosol to the nucleus that leads to ER stress via XBP1 induction and EC apoptosis. Our study suggests a novel role for endothelial MAGI1 as a link between d-flow and ER stress, both of which are fundamental constituents of atherogenesis.