Mice Liver Sms < Sub > 2 < / Sub > Had Influence On The Stability Of Atherosclerotic Plaques

Objectives To assess the effect of SMS2over-expression on plaque stability in ApoE KO mice.Background Human plasma SM levels are an independent risk factor for coronary heart disease. SMS is the last key enzyme of sphingomyelin (SM) de novo biosynthesis pathway, Sphingomyelin synthase1(SMS1) and SMS2are two isoforms, and the activity of Sphingomyelin synthase2(SMS2) is critical to SM levels in the plasma and the cell membrane. Previous studies showed that elevated SMS2activity increased the atherogenic potential and led to increased aorta plaque area. However, the recent anatomy showed that most old aged had plaque formed on vessel wall with no obvious symptoms. Plaque injury and thrombosis is the real culprit in acute cardiovascular events(ACE). Therefore, compared to controlling the size of plaque, improving plaques stability, preventing vulnerable plaque from damage in atherosclerosis (AS) prevention and treatment of ACE is particularly important. We will further explore the relationship between over-expression of SMS2and AS plaque stability.Methods Recombinant adenovirus vector containing human SMS2cDNA (AdV-SMS2) or the reporter gene GFP cDNA (AdV-GFP) were generated in our lab. The SMS2over-expressed mice model were established by femoral vein injection of AdV-SMS2to ApoE KO mice and the control group were injected with AdV-GFP. Both groups were fed high-fat food for30days. Then we determined plasma lipids, morphologically analysed the atherosclerotic plaque and detect some key mediators closely related to AS plaque stability, such as tissue factor(TF), monocyte chemoattractant protein-1(MCP-1), matrix metalloproteinase-2(MMP-2) and cyclooxygenase-1,-2(COX-1,-2), counted circulating endothelial progenitor cells (EPC) in order to discuss the relationship between over-expression of SMS2and AS plaque stability. And these results will help to confirm SMS2as a new target for improving plaques stability. Results Compared with AdV-GFP group, all experimental results indicated that SMS2over-expression resulted in:1. Liver SMS2mRNA expression were increased by2.5-fold (p<0.001); liver total SMS activity were increased by2.3-fold (p<0.001); plasma LDL-C were increased by1.48-fold (p<0.05); plasma HDL-C were decreased by29%(p<0.05); SM/PC were increased by1.5-fold(p<0.05);2. The area of plaque in murine aorta arch was significantly increased by1.7-fold (p <0.001); and the area of plaque in the whole aorta was significantly increased by1.2-fold (p<0.001);3. The area of necrotic core in the aorta root significantly increased by1.6-fold (p <0.001); and the the content of collagen in the aorta root decreased by17%(p <0.001);4. The mRNA and protein expression of TF, MCP-1and MMP-2were significantly increased (p<0.001);5. Significant rise was detected in both mRNA and protein expression levels of COX-2(p<0.001); in contrast, both mRNA and protein expression levels of COX-1was significantly decreased (p<0.001);6. The number of peripheral EPC was significantly reduced (p<0.001); and the number of EPC colony forming unit decreased by40%(p<0.05).Conclusions The most obvious features of plaque instability are increasing fat nucleus, thinning fibrous cap, increasing inflammatory activity, endothelial function abnormal and blood coagulation mechanism etc. In our study, adenovirus-mediated mouse SMS2over-expression resulted in:increased area of plaques necrotic core and reduced collagen content in the aorta root; increased expression of inflammatory factors such as MCP-1, TF, MMP-2, COX-2; reduced expression of COX-1and number and functions of peripheral endothelial progenitor cells. In one word, over-expression of liver SMS2reduced AS plaque stability and repairing capacity of endothelial layer, significantly. Therefore, SMS2could be a candidate effective target for improving plaques stability, preventing vulnerable plaque from damage in atherosclerosis prevention and treatment of ACE.