Abstract 8: The Membrane-associated Guanylate Kinase Ww and Pdz Domain-containing Protein 1 magi1 is Required for Disturbed Flow-induced Endothelial Inflammation and Atherosclerotic Plaque Formation

Abstract

Rationale: Major chronic inflammatory diseases including inflammatory bowel disease and psoriasis are clinically associated with accelerated atherosclerosis and increased risk of cardiovascular diseases (CVD). Atherosclerosis has long been recognized as an inflammatory process, which is initiated by the inflammation and dysfunction of endothelial cells (ECs). Genome-wide association study (GWAS) has identified a significant association between the deletion in ADAMTS9-MAGI1 locus with inflammatory bowel disease and psoriasis, suggesting a potential involvement of MAGI1 in EC inflammation and its associated events. Objective: To investigate the role and regulatory mechanism of MAGI1 as well as MAGI1 post-translational modification in EC inflammation, after various pro-atherogenic stimuli. Methods and Results: MAGI1 depletion significantly inhibits NF-κB activation and adhesion molecule expression induced by various pro-atherogenic stimuli in both in vitro and in vivo . We show that p90RSK associates with MAGI1 WW and PDZ2 domain, which is a crucial step for EC inflammation. In addition, p90RSK activation independently regulates MAGI1 S741 phosphorylation and K931 de-SUMOylation. While MAGI1 S741 phosphorylation is vital for Rap1 and subsequent NF-kB activation via increasing MAGI1-RAPGEF2 interaction, MAGI1 de-SUMOylation induces p90RSK-MAGI1 nuclear translocation as well as nuclear SENP2 T368 and ERK5 S496 phosphorylation. Those events are critical for EC inflammation. In addition, in partial carotid ligation mouse model, we observed a reduction in size of disturbed flow-induced carotid plaque lesion in Magi1 +/- / Ldlr -/- mice compared to that in Magi1 +/+ / Ldlr -/- mice fed with high fat diet, indicating the crucial role of MAGI1 in regulating EC inflammation and atherosclerosis formation. Conclusion: These data show the essential role of MAGI1 in regulating EC inflammation, and suggest that phosphorylation and de-SUMOylation of MAGI1 induced by p90RSK activation have distinctive mechanisms, leading to EC inflammation.