Role In The Formation Process Of Atherosclerosis. Nrage Gene Studies

Atherosclerosis (AS) refers to the lipid deposition in the intima of artery and its branches, accompanied by vascular smooth muscle cells(VSMCs) in the middle migrating to the intima, proliferating, making the endometrium thicker and formating something like yellow or greyish yellow gruel. Today what is widely accepted is that the endothelial injury, lipid deposition, the resulting inflammation and VSMCs proliferation and migration to the intima is the main cause of AS plaque formation. NRAGE was found by Salhe in 2000 through yeast two-hybrid. It is interacting with the p75NTR and belongs to melanoma antigen family.In the experiment, we found that when we inducted VSMC to proliferate with Ang II in vitro, NRAGE expression level was decreased. After treating VSMCs with 5 deoxy-azacytidine for 72h, the expression level of NRAGE was increased, indicating that as the VSMCs proliferated, NRAGE expression level was decresed, and DNA methylation might be one way to lower the level of NRAGE. Similarly, in our rat experiments in vivo, along with the induction of high fat diet, NRAGE expression level was reduced in the time-dependent way, indicating that NRAGE might play a role as anti-AS. When we inducted the formation of AS plaque in Knockout mice with high-fat and cholesterol diet for 3 months, we found that the mouse of knock-out group's thoracic aorta elastic membrane were thicker. The possible mechanisms were under studied. None fatty plaques was found in wild or knockout mice, which may be due to that high fat and cholesterol diet was not a stable method in inducing the formation of AS. The other reason might be that the fodder was not being produced well enough. Besides, we also found that the NRAGE homozygous knock out female mouse were apt to produce lipid deposition, indicating that NRAGE might took place of estrogen-related inflammation. In the later experiment, we will try to use double gene knock-out mouse, such as NRG/ApoE and NRG/LDLR, or use homozygous knock out female mouse to induce AS plaque.