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There is now a CONTENT FREEZE for Mercury while we switch to a new platform. It began on Friday, March 10 at 6pm and will end on Wednesday, March 15 at noon. No new content can be created during this time, but all material in the system as of the beginning of the freeze will be migrated to the new platform, including users and groups. Functionally the new site is identical to the old one. webteam@gatech.edu
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Dr. Hanjoong Jo (Advisor, BME)
Dr. Xiaodong Cheng (Emory Biochemistry)
Dr. Larry McIntire (BME)
Dr. Gregory Gibson (Georgia Tech Biology)
Dr. Michael Davis (BME)
Atherosclerosis is an inflammatory disease that preferentially occurs in disturbed flow exposed regions of arteries. Previous studies indicated that disturbed flow led to pro-inflammatory responses in endothelial cells, but the detailed mechanism was not fully elucidated. An in vivo mouse partial carotid ligation model was recently developed in our lab to study the mechanism of how flow disturbance causes endothelial dysfunction and atherosclerosis. By comparing the RNA profile from flow-disturbed carotid intima with laminar flow exposed carotid intima, we identified and validated 588 mechanosensitive genes. DNMT1, one of the most important DNA methyltransferase in mammals, was identified as an induced gene by the disturbed flow. The up-regulation of DNMT1 was also confirmed in cone-and-plate model with cultured HUVEC cells by oscillatory shear stress. More importantly, 5-aza-2’-deoxycytidine, the pan-DNMT inhibitor, was able to block atherosclerosis formation in multiple mouse atherosclerosis models. Based on these results, we hypothesize that disturbed flow stimulates DNMT1 expression and activity, leading to DNA hypermethylation and silencing of anti-atherogenic mechanosensitive genes, which in turn induces endothelial dysfunction and atherosclerosis. In vitro and in vivo studies were designed to study how DNMT1 was induced, the change of DNA methylation profile, the subsequent endothelial functions and the role of DNMT inhibitors in atherosclerosis in four coherent aims.
