Tiaozhi Tongmai Granules reduce atherogenesis and promote the expression of ATP-binding cassette transporter A1 in rabbit atherosclerotic plaque macrophages and the liver

摘要

Objective:ATP-binding cassette transporter A1(ABCA1)is an integral membrane protein that plays a key role in cellular lipid metabolism,preventing the accumulation of lipids that contribute to the initiation and progression of atherosclerosis.Tiaozhi Tongmai Granules are a Chinese herbal compound that is capable of treating atherosclerosis.This study was designed to explore the potential pharmacological mechanism by which Tiaozhi Tongmai Granules protect against atherosclerosis.Methods:Forty-nine male New Zealand rabbits were randomly divided into seven groups:normal control group,normal diet;model groups 1 and 2:balloon injury and high-fat diet for 6 or 12 weeks;statin groups 1 and 2:balloon injury and high-fat diet plus atorvastatin for 6 or 12 weeks;and Chinese herb groups 1 and 2:balloon injury and high-fat diet plus Tiaozhi Tongmai Granules for 6 or12 weeks.The granules were administered at a dose of 1.14 g/kg/d,with atorvastatin(1.14 mg/kg/d)serving as positive control.Serum lipid profiles and liver function indices were measured.Atherogenesis was viewed after H&E staining and quantified by thickened intimal area percentage and maximal intimal thickness percentage.The ABCA1 protein expression in atherosclerotic plaque macrophages of the common carotid arteries(CCA),thoracic aortae(TA),and liver tissues were observed by immunohistochemical staining and evaluated using mean optical density(OD)value in macrophages and ABCA1-positive hepatocyte number.Results:Compared with model group 1 at week 6,Chinese herb group 1 and statin group 1 displayed significant reductions in total cholesterol(TC)(PZ0.027,0.012)and low-density lipoprotein cholesterol(LDL-C)(PZ0.039,0.028)levels,as well as marked increases in ABCA1-positive hepatocyte numbers(P all<0.001),and only statin group 1 displayed a markedly reducedmaximal intimal thickness percentage in the CCA(P Z 0.018).Compared with model group 2 at week 12,Chinese herb group 2 and statin group 2 all presented significant reductions in TC(P Z 0.011,0.003),LDL-C(P Z 0.017,0.010)and thickened intimal area percentage in the CCA(P Z 0.001,0.022),as well as prominent increases in the ABCA1 OD value of both the CCA(P Z 0.001,0.039)and TA(P Z 0.001,0.025)and positive hepatocyte number(P all<0.001).Chinese herb group 2 had a markedly reduced maximal intimal thickness percentage compared with model group 2(P Z 0.006)and a higher positive hepatocytes number than statin group 2(P Z 0.001).Conclusions:Tiaozhi Tongmai Granules appear to have an anti-atherogenic effect that is most likely mediated by simultaneously upregulating the protein expression of ABCA1 in rabbit atherosclerotic plaque macrophages and in the liver.