| Background:Atherosclerosis (AS) is a serious cardiovascular disease, which has high death rate and many predisposing factors. At present, in view of its pathogenesis, a variety of theories have been put forward, mainly including inflammation, plaque theory and so on. Inflammation hypothesis argues the development and evolution of AS is an inflammatory process, and many inflammatory cells, cytokines play important roles in this process. Plaque theory thinks that unstable plaque tends to rupture easily, and plaque rupture would be affected by many factors and lead to thrombosis and vascular congestion and other serious consequences. In addition, fatty liver disease can promote the occurrence and development of AS. An important induced factor of fatty liver disease is oxidative stress, which involved a variety of oxidative stress related enzymes.Apolipoprotein A-I (apoA-I) is the main protein component and function implementation of human high density lipoprotein (HDL). Many studies have shown that apoA-I can inhibit atherosclerosis, through participating in reverse cholesterol transport, plaque remodeling, and its anti-inflammatory, anti-oxidant, anti-thrombotic and membrane protective effects. But the specific inhibitory mechanism of apoA-I is still not completely understood, which needs to be further studied and improved.Objective:In our study, we used high fat diet method to establish AS rabbit model. We observed the effects of apoA-I on atherosclerosis, including aorta and liver in rabbits. Then we mainly researched the effects of apoA-I on the expression of inflammatory factors in aorta, MMP-2and related regulatory proteins in rabbits and macrophages, and oxidative stress-related enzymes in liver. Moreover, we preliminarily explored the possible mechanisms of apoA-I in inhibiting AS and its complications. We hope to provide new theoretical basis and research direction for the application of apoA-I to clinical treatment of AS.Methods:Experimental animals were male New Zealand white rabbits (8weeks old, weight1.9～2.3kg).50rabbits were randomly divided into normal group, model group, apoA-I (20mg/kg/w) group, apoA-I (40mg/kg/w) group and Lipitor group. Except for the normal group, other groups were fed with high fat diet, and given different drugs regularly. Then following indicators were observed:(1) Contents of TC, TG, HDL-C and LDL-C in serum and liver were detected by specific kits.(2) The morphological, histological and pathological changes in aorta and liver were observed.(3) The contents of ICAM-1, VCAM-1, MCP-1, TGF-α, IL-6and CRP in serum and aorta were detected by ELISA method. And the mRNA expression of VCAM-1, IL-6, COX-2and NF-κB in aorta was determined by PCR method.(4) The expression of MMP-2, PPAR α/γ, COX-2and NF-κB in aorta and THP-1cell derived macrophages was detected by immunohistochemical method, PCR method, ELISA method and Western blot method.(5) The contents of PGE2and PGD2, and the mRNA expression of L-PGDS in THP-1cell derived macrophages were measured by ELISA and PCR method.(6) Liver MDA content, activities of SOD, GPx and iNOS were determined with specific kits. The mRNA expression of SOD, GPx and CAT in liver was detected by PCR method.Results:(1) ApoA-I reduced serum lipid levels, aortic plaque area and aortic injury degree in AS rabbits.(2) ApoA-I decreased the content of liver lipids, liver coefficient, and liver injury degree in AS rabbits.(3) ApoA-I reduced the content and mRNA expression of related inflammatory in aorta of AS rabbits.(4) ApoA-I inhibited the expression of MMP-2, COX-2and NF-κB, and increased the expression of PPAR α/γ in aorta of AS rabbits and macrophages.(5) ApoA-I increased the protein expression of PGE2, PGD2and mRNA expression of L-PGDS in macrophages.(6) ApoA-I reduced MDA content and iNOS activity; and increased SOD, GPx activity and mRNA expression of SOD, GPx and CAT in liver of AS rabbits.Conclusion:AS rabbit model was successfully established by high fat diet, apoA-I has inhibitory effects on AS and fatty liver in rabbits. The anti-atherosclerotic effects of apoA-I may be related to the following effects:(1) anti-inflammatory effect, which may be achieved by reducing the content of ICAM-1, VCAM-1, MCP-1, TGF-a, IL-6and CRP, and mRNA expression of VCAM-1, IL-6, COX-2and NF-γB;(2) inhibitory effect on MMP-2, which may be achieved by influencing the expression of PPAR α/γ, COX-2and NF-κB, and this effect may be helpful in stabling plaques;(3) vascular-protective effect, which is possibly achieved through increasing PGE2and PGD2expression;(4) inhibitory effect of apoA-I on fatty liver and antioxidant effect, which is possibly achieved through improving the effects of SOD, GPx, CAT, and decreasing iNOS activity. |
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