MAGI1 as a link between endothelial activation and ER stress drives atherosclerosis
Jun-ichi Abe, … , Scott E. Evans, Nhat-Tu Le
Jun-ichi Abe, … , Scott E. Evans, Nhat-Tu Le
Published April 4, 2019
Citation Information: JCI Insight. 2019;4(7):e125570. https://doi.org/10.1172/jci.insight.125570.
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Research Article Cardiology Cell biology

MAGI1 as a link between endothelial activation and ER stress drives atherosclerosis

Abstract

The possible association between the membrane-associated guanylate kinase with inverted domain structure-1 (MAGI1) and inflammation has been suggested, but the molecular mechanisms underlying this link, especially during atherogenesis, remain unclear. In endothelial cells (ECs) exposed to disturbed flow (d-flow), p90 ribosomal S6 kinase (p90RSK) bound to MAGI1, causing MAGI1-S741 phosphorylation and sentrin/SUMO-specific protease 2 T368 phosphorylation-mediated MAGI1-K931 deSUMOylation. MAGI1-S741 phosphorylation upregulated EC activation via activating Rap1. MAGI1-K931 deSUMOylation induced both nuclear translocation of p90RSK-MAGI1 and ATF-6-MAGI1 complexes, which accelerated EC activation and apoptosis, respectively. Microarray screening revealed key roles for MAGI1 in the endoplasmic reticulum (ER) stress response. In this context, MAGI1 associated with activating transcription factor 6 (ATF-6). MAGI1 expression was upregulated in ECs and macrophages found in atherosclerotic-prone regions of mouse aortas as well as in the colonic epithelia and ECs of patients with inflammatory bowel disease. Further, reduced MAGI1 expression in Magi1–/+ mice inhibited d-flow–induced atherogenesis. In sum, EC activation and ER stress–mediated apoptosis are regulated in concert by two different types of MAGI1 posttranslational modifications, elucidating attractive drug targets for chronic inflammatory disease, particularly atherosclerosis.

Authors

Jun-ichi Abe, Kyung Ae Ko, Sivareddy Kotla, Yin Wang, Jesus Paez-Mayorga, Ik Jae Shin, Masaki Imanishi, Hang Thi Vu, Yunting Tao, Miguel M. Leiva-Juarez, Tamlyn N. Thomas, Jan L. Medina, Jong Hak Won, Yuka Fujii, Carolyn J. Giancursio, Elena McBeath, Ji-Hyun Shin, Liliana Guzman, Rei J. Abe, Jack Taunton, Naoki Mochizuki, William Faubion, John P. Cooke, Keigi Fujiwara, Scott E. Evans, Nhat-Tu Le

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Figure 7

MAGI1 expression in d-flow–induced atherosclerosis and in colonic tissues of IBD patients.

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MAGI1 expression in d-flow–induced atherosclerosis and in colonic tissue...
(A) Representative images of H&E-stained sections of LCA and RCA samples obtained from NLC/Ldlr–/– and Magi1+/–/Ldlr–/– mice after 4 weeks of partial LCA ligation. Scale bars: 200 μm. (B) The intima/media ratios in H&E-stained LCA sections (18). Data represent mean ± SEM for NLC/Ldlr–/– (n = 15) and Magi1+/–/Ldlr–/– (n = 19) mice. *P < 0.05. (C and D) Aortas were harvested from Magi1+/+/Ldlr–/– HFD-fed mice. En face preparations of aortas were coimmunostained with anti–VE-cadherin (green) and -MAGI1 (red) antibodies. (C) Aorta areas exposed to l-flow or d-flow. The boxed areas are magnified below. Scale bars: 20 μm. (D) Histogram of MAGI1 staining in d-flow (DF) and l-flow (LF) regions in NC-fed WT mice and HFD-fed Ldlr–/– mice. Data represent mean ± SEM (n = 5–10/group). *P < 0.05. (E and F) Aortas were harvested from NC-fed WT C57BL/6 mice. (F) En face preparations of aortas were coimmunostained with anti–VE-cadherin (green) and anti-phospho–specific MAGI1-S741 (red) antibodies. (E) Histogram of phospho-specific MAGI1-S741 staining. Data represent mean ± SEM (n = 8–10/group). **P < 0.01. (G–I) Paraffin-embedded sections of colonic tissue samples obtained from patients with UC or CD and control patients without IBD were immunostained with anti-MAGI1 (red), anti-CD31 (green), and DAPI (blue). (G) More intense MAGI1 staining at the luminal surface in colonic epithelium samples obtained from CD and UC patients compared with those obtained from normal controls. The boxed area is magnified at right and shows colocalization of CD31 and MAGI1. Scale bars: 50 μm; 20 μm (zoom inset). (H) The intensity of the MAGI1 staining at the luminal surface in each sample was determined using ImageJ. Data represent mean ± SEM (n = 15–18/group). *P < 0.05. (I) Colocalization of CD31 and MAGI1 at the vessels in the samples was assessed using Pearson’s correlation coefficient. CD31 staining structures were excluded when we could not clearly identify them as vessels. Data represent mean ± SEM (n = 6–17/group). **P < 0.01. Statistical differences between 2 independent groups (B and E) were assessed using the 2-tailed Student’s t test and 1-way ANOVA followed by Bonferroni’s post hoc testing for multiple groups (D, H, and I).