Combined Inhibitory Effects Of Fluvastatin And Losartan On Atherosclerosis And Plaque Inflammation In Rabbits

[Objective] There is increasing evidence of cross-talk between rennin-angiotensin system(RAS) and dyslipidemia in atherosclerosis. We postulated that inhibition of RAS with losartan and dyslipidemia with fluvastatin would have additive inhibitory effect on plaque inflammation and atherosclerosis.[Methods] Forty-four male New Zealand white rabbits were randomly and equally assigned to 5 groups: control group (n=8),fed with normal diet; high-cholesterol group (n=9),fed with high-cholesterol diet alone; fluvastatin-treated group (n=9),fed with high-cholesterol diet and treated with fluvastatin(10mg/kg/day); losartan group(n=9),fed with high-cholesterol diet and treated with losartan(25mg/kg/day); fluvastatin + losartan group(n=9),fed with high-cholesterol diet and treated with fluvastatin(10mg/kg/day) + losartan(25mg/kg/day). They were fed for 4 months, the thoracic aorta were harvested, the concentration of serum total cholesterol were measured. We used HE staining to observe the morphology of thoracic aorta and immunohistochemical staining to measure the alteration of macrophage and vascular smooth muscle cell and MCP-1.The MCP-1 mRNA was analyzed by RT-PCR.[Results] 1. The concentration of serum TC in high-cholesterol group and all drug-treated groups at 4 months was significantly higher than that of control group. The concentration of serum TC in fluvastatin-treated group was significantly decreased than that of high-cholesterol group (P<0.01). Compared the concentration of serum TC in losartan group with that in high-cholesterol group, there was no statistical difference in losartan group and in high-cholesterol group (P>0.05). However, the combined feeding of fluvastatin and losartan have no additive effect compared with fluvastatin alone (P>0.05).2. The morphology of the thoracic aorta: The vessel structure of thoracic aorta in control group was normal and there was no plaque in it.Fluvastatin and losartan alone decreased the extent of atherosclerosis, however, the combined feeding of fluvastatin and losartan reduced atherosclerosis in an additive fashion.3. The observation of immunohistochemical staining section: Through quantitative analysis, fluvastatin and losartan alone significantly decreased the infiltration of macrophage and the expression of MCP-1 (P＜0.01 respectively), the combined feeding of fluvastatin and losartan have an additional reduction in the infiltration of macrophage and the expression of MCP-1 than fluvastatin and losartan alone (P＜0.01 and P＜0.05 respectively).4. The observation of RT-PCR: Fluvastatin and losartan alone significant decreased the relative value of MCP-1 mRNA (P<0.01 respectively), the combined feeding of fluvastatin and losartan have an additional reduction in the expression of MCP-1 mRNA than fluvastatin and losartan alone (P<0.05).[Conclusion] 1. The combined feeding of fluvastatin and losartan have an additional reduction in the extent of atherosclerosis than fluvastatin and losartan alone.2. The combined feeding of fluvastatin and losartan have an additional reduction in the infiltration of macrophage and the expression of MCP-1 protein than fluvastatin and losartan alone.3. The combined feeding of fluvastatin and losartan have an additional reduction in the expression of MCP-1 mRNA than fluvastatin and losartan alone.