Rapid Establishment Of Hamster Models Of Hyperlipidemia/atherosclerosis And The Application Of Key Technique For Pharmacodynamics Evaluation

Hyperlipidemia and atherosclerosis are the major risking factors of cardiovascular disease. Humanlike, repeatable and standardized anima models for hyperlipidemia and atherosclerosis are well needed for the study of those diseases and the development of new drugs.Several species of animals have been used to construct animal models for hyperlipidemia/atherosclerosis while so far none of them are ideal because of low response to dietary cholesterol or sharing few common characteristics with human in lipid metabolism. Compared with other rodent animals such as rat and mouse, hamster is considered much more humanlike in the lipid metabolism. In our sudy hyperlipidemia and atherosclerosis were induced rapidly in hamsters by feeding on high fat/cholesterol diet (HFHC diet) and extra-high fat/cholesterol (extra-HFHC diet) respectively. We analized the serum lipids of the hamster model for hyperlipidemia after 0,1,2,3,6,9, 12,15,18,21,26,34 and 42 weeks and for atherosclerosis after 0,3,6,9,14,16,21,24and 42 weeks of dietary intervention. The characteristics of lipoproteins, pathology of important organs and the expression of key proteins involved in the lipid metabolism were studied via Fast Protein Liquid Chromatography, histochemistry and molecular biological techniques at the short term (4 week), middle term (21 week) and long term (42 week) groups of animal model. A tentative research on the variation among hamster, rat and human were also conducted in our present study.The results show:① After feeding on HFHC diet for 1 week hamsters had significantly elevated VLDL-C, LDL-C, HDL-C and TG, which went on increasing until the 18th week and then reached a platu. Those serum lipid levels in the hamster model for atherosclerosis rised more rapidly and reach to a higher degree in the first 3 weeks than hamster model for hyperlipidemia, then also decreased to a platu.② At the short term of hyperlipidemia, The VLDL and LDL increased significantly while the HDL remain unchanged. At the middle and long term of hyperlipidemia the VLDL kept significantly higher, HDL came to a significantly lower level than animals fed on control diet. Within the middle and long term groups of animals fed on Extra-HFHC diet, VLDL and LDL level both significantly elevated while HDL level remained unchanged. The capacity of carrying cholesterol of HDL is significantly raised for the model animals of atherosclerosis in the middle term and showed no changes in the long term, which inferred a turn for the worse of the dysplipidemia.③ The hamsters among both the model groups developed fatty liver and this condition deteriorated when the hamsters went on feeding on the proatherogenic diets as shown by both ultrasonic imaging and histochemical methods. The maximum thickness of intima-media membrane (IMT) of the aortic arch grew significant in the middle and long term groups of hamsters model for hyperlipidemia. Plaques was discovered in the aortic arch and aortic root among the model hamsters for atherosclerosis after 21 weeks on Extra-HFHC diet and the amount and size grew after another 21 weeks.④ Typical cytokines which were regarded important for the development of atherosclerosis were analyzed using ELISA kits and the whole blood analyses were performed by hematology analyzer. It was found that TNF-α andIL-10 were significantly elevated at the fourth week on HFHC diet. Among hamsters fed on extra-HFHC diet for 21 weeks the amount of IL-β was decreased while the level of TNF-a increased, and the amount of white cells, neutrophils and eosinophils rised significantly. At the 42nd week on extra-HFHC diet all the cytokines levels of TNF-a, IL-10, IL-(3 and IL-6 decreased significantly compared with the those in the control hamsters.⑤ The expression of SREBP2 in both model hamsters were inhibited in different periods. After different periods of HFHC dietary intervention the expression of HMGCR showed no changes. The expression of SR-BI of hamsters fed on HFHC at the early term increased, then decreased as well as the expression of LDL-R and SOAT1 at later periods. When at the 42nd week on HFHC diet levels of ABCAl went up while the expression of LCAT went down. For the hamsters maintained on extra-HFHC diet, the expression of HMGCR didn’t changed significantly, LDL-R and CYP7A1 decreased and ABCAl increased at the 21st week. At the 42nd week the levels of SREBP2,HMGCR,LDL-R,SR-BI,SOAT1 and CYP7A1 decreased and the levels of ABCAl increased significantly.⑥ By comparing the charateristics in the response to dietary fat and the profiles of serum lipoproteins, we concluded that hamsters were much more humanlike than rats and it was preferable for hamster to be used as animal models of hyperlipidemia and atherosclerosis. In our present study we constructed hamster models for hyperlipidemia and atherosclerosis by dietary intervention, performed systemic exploratory research on the varying pattern of serum lipids, characteristics of the profiles of lipoprotein, the pathology of important organs and the time dependent changes of key proteins in lipid metabolism, and aim to facilitate these animal models as useful tools in developing new drugs. Our work had been exploratory and much more study was needed if these models were to be pursued as standardized, repeatable and humanlike animal models for pharmacological and nutritional studies.With our tentative study of multiple characteristics of hamster in serum lipid, lipoprotein profile, the pathology of organs sensitive to fatand the expression of relevant proteins,we conclude that it is feasible and reliable to use hamster as animal models of diet-induced hyperlipidemia and atherosclerosis.