Effects And Mechanisms Of Artesunate As An Adjuvant Blood Lipid Lowering

Objective: Chinese medicine thinks that atherosclerosis is caused by the toxin,"foreign poison invasion, innate poison metaplasia", leading to organ dysfunction andthe formation of phlegm and stasis, and finally to the formation of atheroscleroticplaque. Traditional Chinese medicine with detoxification efficacy can be used for theprevention and treatment of atherosclerosis. Artemisia annua is one of traditionalChinese medicine and has been used for heat, cooling blood, detoxification, treatingmalaria. Artesunate is one of derivatives of artemisinin that is the main activeingredient of Artemisia annua, and has a variety of pharmacological effects ofanti-inflammation and immunosuppresion that meet the treatment policy developedaccording to atherosclerotic inflammation doctrine. Considering the efficacy ofArtemisia annua and pharmacological effects of artesunate, we think that artesunateshould have lower lipid and anti-atherosclerotic potential, but few studies of thisaspect were done, especially in the whole animal study. In this study, we investigatedthe effect and mechanism of artesunate on hyperlipidemia and atherosclerosis.Methods: In this study, rats, mice, hamsters and rabbits were used to evaluatethe anti-atherosclerotic effects of artesunate alone and in combination with otherlipid-lowering medicine; gene chip technology and Western-blot technique were usedto study its effect on the expression of atherosclerosis-related genes and proteins, toexplore its mechanism of action.Results: Artesunate reduced the serum triglyceride levels, but no significanteffect on cholesterol level was measured in hyperlipidemia rats. The combination withursolic acid reduced not only serum cholesterol, triglycerides and low-densitylipoprotein, but also liver lipid. In the rabbit model induced by high fat diet,artesunate decreased blood levels of total cholesterol by47%, triglyceride by63%, and of LDL, and increased high density lipoprotein. The artesunate combined withursolic acid showed better therapeutic effect, superior to not only artesunate andursolic acid alone, but also the positive control drug atorvastatin. Artesunate reducedthe rabbit hepatic steatosis degree and reduced the area of the aorticatherosclerotic plaque. Combined use of artesunate with ursolic acid prevented fattyliver and atherosclerosis formation. Similarly, in apoE knockout mouse model,artesunate could also reduce serum total cholesterol and triglycerides, and the resultsof overall oil red staining and cross-section oil red staining of aorta showed thatartesunate may reduce atherosclerotic plaque area; better result was found in thecombination of artesunate with atorvastatin, while the same dose of atorvastatin aloneexhibited no effect on serum cholesterol levels. Lipid-lowering effect of artesunatewas confirmed in Syrian golden hamster model; the combination of artesunate withursolic acid or atorvastatin exhibited superior effect to any kind of drugs alone.Atorvastatin elevated serum AST/ALT ratio of golden hamster, showing some toxicityin liver, and the combination with artesunate significantly decreased the AST/ALTratio. Artesunate alone and in combination with ursolic acid did not exhibit significantliver toxicity.The aortic functional genome chip analysis in apoE gene knockout mouseshowed that the expression of apoA-I gene in artesunate group was raised by4.98times compared with model group. Moreover, IL-5increased by4times, Itgaxreduced by4.2times, and Vwf and Tnc reduced more than3times. In addition toincreased level of apoA-I by artesunate and reduced level of Ifng by atorvastatin,combined use of both drugs raises KLF2gene by3times as well. In rabbit liver,artesunate raised apoA-I gene expression, and ursolic acid upregulated the expressionof PPAR-α gene; SREBP1and LDLR were raised only when artesunate and ursolicacid were combined. Finally, artesunate raised the protein levels of apoA-I in therabbit liver, and only the combination of artesunate and ursolic acid increased theexpression of liver LDLR protein.Conclusion: In summary, artesunate can decrease blood lipid, prevent theformation of atherosclerotic plaque in a variety of hyperlipidemia and atherosclerosis models. The results of genome chip and western-blot showed that artesunate raisedthe level of apoA-I, IL-5and KLF2, reduced Itgax, Vwf and Tnc. ApoA-I and KLF2were new target of artesuante that were found in our study. Therefore, based on theresults of pharmacodynamic and molecular mechanism, artesunate has the potential tobecome a new lipid-lowering drug.