| Atherosclerosis is a chronic inflammatory disease, accompanied by the production of a wide range of chemokines, cytokines, and vascular growth factors. Recent studies have demonstrated that transcription factor nuclear factor kappaB (NF-κB) is an important mediator of the inflammatory processes,which could regulate many of the inflammatory genes linked to atherosclerosis. Different stimuli can induce the activation of NF-κB, including hypercholesterolemia and the tissue renin-angiotensin system (RAS) that lead to the NF-κB mediated expression of chemokine,adhesion molecule,cytokine,growth factor and various other inflammatory mediators subsequently leading to the development of atherosclerosis.Several drugs are known to modulate the processes of inflammation and possibly the process of atherogenesis. Among them are 3-hydroxy-3-methyl-glutaryl CoA (HMG-CoA) reductase inhibitor, angiotensin-converting enzyme inhibitors (ACEI) and nonsteroidal anti-inflammatory drug. Although these drugs are associated with a reduction of cardiovascular events, the effect of systemic administration of these drugs on the local inflammatory pathway within the atherosclerotic plaque is not extensively studied.In this study, we investigated the effects of HMG-CoA reductase inhibitor- simvastatin, ACEI-enalapril and nonsteroidal anti-inflammatory drug-aspirin on the serum lipids and the level of hs-CRP, NF-κB-DNA binding activity, expression of MCP-1, MMPs, COX-2 in atherosclerotic plaque in rabbit models and tried to explore the anti-atherosclserotic mechanism of these drugs. Part I Effects of Simvastatin on NF-κB-DNA Binding Activity and Inflammatory Mediators Expression in a Rabbit Model of AtherosclerosisObjective:To observe the effects of simvastatin on NF-κB-DNA binding activity,on the expression of monocyte chemoattractant protein-1 (MCP-1), CD68 and tumor necrosis factor-alpha (TNF-a) in atherosclerotic plaque and on the levels of hs-CRP in rabbits and to explore the anti-atherosclerotic properties beyond its lipid-lowering effects.Methods:Thirty-six New Zealand male rabbits were randomly divided into low-cholesterol group (LC), high-cholesterol group (HC), high-cholesterol+simvastatin group (HC+S) and then were fed for 12 weeks. During the experiment, the levels of serum TC, TG and LDL-C were examined. At the end of the experiment, standard enzymatic assays, enzyme-linked immunosorbent assay (ELISA), electrophoretic mobility shift assay (EMSA), reverse transcription polymerase chain reaction (RT-PCR),immunohistochemistry staining and morphometry were performed to assess the serum lipids, hs-CRP, NF-κB-DNA binding activity, TNF-a mRNA , TNF-a and MCP-1 protein expression, CD68 positive macrophages, neointima thickness and plaque area of aorta respectively in all three groups.Results:Our results showed that the serum lipids, the level of hs-CRP, the NF-κB-DNA binding activity, the expression of MCP-1, CD68 and TNF-a, the neointima thickness and plaque area of aorta in the LC and HC+S groups were significantly lower than those in the HC group (P<0.05). There was no significant difference in the serum lipids between the LC and HC+S groups (P>0.05), but the level of hs-CRP, the NF-κB-DNA binding activity, the expression of MCP-1, CD68 and TNF-a, the neointima thickness and plaque area of aorta in the HC+S group were significantly decreased compared to the LC group (P<0.05).Conclusion : This study demonstrates that simvastatin could decrease atherosclerosis by inhibiting the NF-κB-DNA binding activity, by reducing the levels of hs-CRP and by reducing the expression of MCP-1, CD68 and TNF-a.Part II Effects of Enalapril on NF-κB-DNA Binding Activity in a Rabbit Model of AtherosclerosisObjective: To observe the effects of enalapril on levels of Angiotensin II (Ang II), hs-CRP, NF-κB-DNA binding activity and on the expression of Angiotensin II receptor 1(AT1), NF-κB, monocyte chemoattractant protein-1 (MCP-1) and CD68 in atherosclerotic plaque in rabbits and to explore it's anti-atherosclerotic mechanisms.Methods: Thirty-six New Zealand male rabbits were randomly divided into normal group (NC), high-cholesterol group (HC), high-cholesterol+enalapril group (HC+E) and then were fed for 12 weeks. At the end of the experiment, standard enzymatic assays, radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), electrophoretic mobility shift assay (EMSA), immunohistochemistry staining and morphometry were performed to observe serum lipids, the levels of Ang II and hs-CRP, the NF-κB-DNA binding activity, the NF-κB , AT1, MCP-1 protein expression and the CD68 positive macrophages, the neointima thickness and plaque area of aorta respectively in all three groups.Results: Our results showed that the serum lipids, the levels of Ang II and hs-CRP, the NF-κB-DNA binding activity, the expression of NF-κB, AT1, MCP-1 protein and the CD68 positive macrophages, the neointima thickness and plaque area of aorta in the HC and HC+E groups were significantly increased than those in the NC group (P<0.05). There was no significant difference in the serum lipids between the HC and HC+E groups (P>0.05), but the levels of Ang II and hs-CRP, the NF-κB-DNA binding activity, the expression of NF-κB, AT1, MCP-1 protein and the CD68 positive macrophages, the neointima thickness and plaque area of aorta in the HC+S group were significantly decreased compared to the HC group (P<0.05). Conclusion: This study demonstrates that the renin-angiotensin system may play an important role in the pathogenesis of atherosclerosis. Enalapril could decrease atherosclerosis by inhibiting the levels of Ang II, inhibiting the NF-κB-DNA binding activity and by reducing the expression of NF-κB , AT1, MCP-1 protein and the CD68 positive macrophages .Part III Effects of Aspirin on NF-κB-DNA Binding Activity and COX-2,MMPs Expression in a Rabbit Model of AtherosclerosisObjective: To observe the effects of aspirin on NF-κB-DNA binding activity and the expression of cyclooxygenase-2(COX-2),matrix metalloproteinase-1,9(MMP-1,9 ) in atherosclerotic plaque in rabbits and to explore it's anti-atherosclerotic mechanisms .Methods: Thirty-six New Zealand male rabbits were randomly divided into normal group (NC), high-cholesterol group (HC), high-cholesterol+aspirin group (HC+A) and then were fed for 12 weeks. At the end of the experiment, standard enzymatic assays, enzyme-linked immunosorbent assay (ELISA), electrophoretic mobility shift assay (EMSA), immunohistochemistry staining, and morphometry were performed to observe serum lipids, the levels of hs-CRP, the NF-κB-DNA binding activity, the expression of NF-κB, COX-2 and MMP-1,9 protein, the neointima thickness and plaque area of aorta respectively in all three groups.Results: Our results showed that the serum lipids, the levels of hs-CRP, the NF-κB-DNA binding activity, the expression of NF-κB, COX-2 and MMP-1,9 protein expression, the neointima thickness and plaque area of aorta in the HC and HC+A groups were significantly increased than those in the NC group (P<0.05). There was no significant difference in the serum lipids between the HC and HC+A groups (P>0.05), but the levels of hs-CRP, the NF-κB-DNA binding activity, the expression of NF-κB, COX-2 and MMP-1,9 protein expression, the neointima thickness and plaque area of aorta in the HC+A group were significantly decreased compared to the HC group (P<0.05).Conclusion: This study demonstrates that aspirin could decrease atherosclerosis by inhibiting the NF-κB-DNA binding activity and by reducing the expression of COX-2 and MMP-1,9.
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