Zhao Shui-ping, Wu Zhi-hong, Wu Jie, Hong Shao-cai, Deng Ping
Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, PR China.
J Cardiovasc Pharmacol. 2005 Aug;46(2):185-9. doi: 10.1097/01.fjc.0000167017.69468.61.
Tumor necrosis factor alpha (TNFalpha) is an inflammatory cytokine involved in atherogenesis. Adipose tissue is an important source of endogenous TNFalpha production. The aim of this study was to evaluate the effect of atorvastatin on TNFalpha serum concentration and mRNA expressions of subcutaneous adipose in hypercholesterolemic rabbits. Sixteen rabbits fed with a high-cholesterol diet for 8 weeks were randomly divided into 2 groups: (1) the high-cholesterol group (n=8) was maintained on a high-cholesterol diet for 6 weeks; (2) the atorvastatin group (n=8) had the same high-cholesterol diet plus atorvastatin (2.5 mg/kg/d) for 6 weeks. A control group (n=5) was fed with a normal diet for 14 weeks. Subcutaneous adipose was collected for mRNA analysis. Additionally, the direct effect of atorvastatin on TNFalpha release and mRNA expression was assayed in primary rabbit adipocytes. TNFalpha levels in serum and adipocyte culture supernatant were measured by ELISA. RT-PCR was used to evaluate TNFalpha mRNA expression in adipose and adipocytes. Serum TNFalpha concentration was significantly associated with serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) (both P<0.01). Compared with the control group, rabbits fed with a high-cholesterol diet showed higher levels of TNFalpha serum concentration and mRNA expression of adipose, both of which were significantly reduced by atorvastatin treatment (both P<0.05). TNFalpha mRNA expressions of adipose were significantly correlated with circulating TNFalpha levels among the 3 groups (r=0.51, P<0.05). Atorvastatin dose-dependently inhibited lipopolysaccharide (LPS)-induced TNFalpha secretion and mRNA expression in cultured adipocytes. In conclusion, atorvastatin can directly inhibit TNFalpha expression and secretion in adipocytes. Atorvastatin reduced TNFalpha serum concentration in hypercholesterolemic rabbits, which might be because of its cholesterol-lowering effect and direct inhibition of TNFalpha expression in adipose.
肿瘤坏死因子α（TNFα）是一种参与动脉粥样硬化形成的炎性细胞因子。脂肪组织是内源性TNFα产生的重要来源。本研究旨在评估阿托伐他汀对高胆固醇血症兔血清TNFα浓度及皮下脂肪mRNA表达的影响。将16只喂食高胆固醇饮食8周的兔子随机分为2组：（1）高胆固醇组（n = 8）继续喂食高胆固醇饮食6周；（2）阿托伐他汀组（n = 8）在相同的高胆固醇饮食基础上加用阿托伐他汀（2.5 mg/kg/d）6周。对照组（n = 5）喂食正常饮食14周。收集皮下脂肪用于mRNA分析。此外，在原代兔脂肪细胞中检测阿托伐他汀对TNFα释放及mRNA表达的直接作用。采用酶联免疫吸附测定法（ELISA）检测血清及脂肪细胞培养上清液中的TNFα水平。逆转录聚合酶链反应（RT-PCR）用于评估脂肪及脂肪细胞中TNFα mRNA表达。血清TNFα浓度与血清总胆固醇（TC）及低密度脂蛋白胆固醇（LDL-C）显著相关（均P < 0.01）。与对照组相比，喂食高胆固醇饮食的兔子血清TNFα浓度及脂肪mRNA表达水平更高，而阿托伐他汀治疗可使其显著降低（均P < 0.05）。3组中脂肪TNFα mRNA表达与循环TNFα水平显著相关（r = 0.51，P < 0.05）。阿托伐他汀可剂量依赖性抑制脂多糖（LPS）诱导的培养脂肪细胞中TNFα分泌及mRNA表达。总之，阿托伐他汀可直接抑制脂肪细胞中TNFα的表达及分泌。阿托伐他汀降低了高胆固醇血症兔的血清TNFα浓度，这可能是由于其降胆固醇作用及对脂肪中TNFα表达的直接抑制作用。
