title: Triptolide inhibits the progression of atherosclerosis in apolipoprotein E-/-mice.
abstract: Atherosclerosis, the major cause of cardiovascular disease, is accompanied by a chronic inflammatory response during the disease. Triptolide (TPL) is an active natural compound that has been demonstrated to possess anti-inflammatory activities in various cell types. However, the effects of TPL on atherosclerosis have not yet been studied. The goal of the present study was to determine the effects of TPL on apolipoprotein E knock-out (ApoE-/-) mice fed with a high-fat diet and to analyze the changes in lipid metabolism and inflammatory cytokines to clarify the underlying molecular mechanisms. Firstly, the genotypes of ApoE-/-mice and corresponding wild-type mice were identified using polymerase chain reaction. The ApoE-/-mice were randomly divided into four groups: ApoE-/-model mice, and ApoE-/-mice treated with 25, 50 or 100 µg/kg TPL every twice day. Wild-type mice with the same genetic background constituted the fifth group. The mice in each group were given a high-fat diet from week 8 after birth until week 20. Total cholesterol and total triglyceride levels were determined at 16 and 20 weeks. The results demonstrated that the levels of total cholesterol and total triglyceride in the plasma were highly increased in ApoE-/-mice models, compared with those of wild-type mice, and the ApoE-/-mice treated with TPL had decreased levels of total cholesterol and total triglyceride in plasma, which exhibited a dose-dependent reduction as the dose of TPL increased. Moreover, the effects of TPL on the production of inflammatory cytokines in macrophages were determined by ELISA. The results demonstrated that the macrophages from ApoE-/-mice produced high levels of the inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and IL-8. However, following treatment with TPL doses of 25, 50 and 100 µg/kg, the cytokine levels were significantly decreased in a dose-dependent manner. Additionally, proteins associated with lipid metabolism were tested by western blotting. The results showed that the expression of anti-ATP-binding cassette transporter A1 in the macrophages of ApoE-/-mice was increased following treatment with TPL. However, the expression levels of LXRα were not markedly changed following treatment of the mice with different doses of TPL. These results suggest that TPL inhibited the progression of atherosclerosis not only by inhibiting the chronic inflammatory response, but also by regulating lipid metabolism, which may provide new insights useful in the clinical therapy of atherosclerosis.
authors.affiliation: Department of Cardiovascular Medicine, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China.
authors.forename: Longfeng
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Cardiovascular Medicine, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China.
authors.forename: Tianlun
authors.initials: T
authors.lastname: Yang
keywords: anti-ATP-binding cassette transporter A1; atherosclerosis; inflammatory cytokines; liver X receptor; triptolide