[Effects of Tongxinluo and Simvastatin on the stabilization of vulnerable atherosclerotic plaques of aorta in aortic atherosclerosis and molecular mechanism thereof: a comparative study with rabbits].
OBJECTIVE
To evaluate the plaque stabilization effects of Tongxinluo and Simvastatin in aortic atherosclerosis, and to explore molecular mechanism.


METHODS
Twenty-three New Zealand white rabbits underwent aortic balloon injury and fed with high-cholesterol diet for 16 weeks and then randomly divided into 3 groups: Tongxinluo group (n = 6, undergoing gastric perfusion of Tongxinluo 1 gxkg(-1)xd(-1)), simvastatin group (n = 9, undergoing gastric perfusion of simvastatin 2 mgxkg(-1)xd(-1)), and model group (n = 8, without drug administration). Another 6 rabbits were used as normal controls. Peripheral blood samples were collected 10 weeks before the administration, and 3 and 16 weeks after the administration to detect the levels of total cholesterol (TG), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), and by the end of experiment peripheral blood samples were collected to detect the levels of serum endothelin (ET) and nitric oxide (NO). Then the rabbits were killed and their aortas were taken out to undergo pathological examination. Western blotting was used to detect the protein expression of Metalloproteinase (MMP)-1 and cyclooxygenase (COX)-2 and RT-PCR was used to detect the mRNA expression of FasL and bcl-2.


RESULTS
By the end of the experiment the levels of blood lipids were raised by 1 approximately 2 times in the normal group (P < 0.05), and raised more significantly in the model and intervention groups (P < 0.05 approximately 0.01), especially the TC level of the model group was raised by 40 tomes. The levels of blood lipids of the simvastatin group were significantly lower than those of the model group (P < 0.05 approximately 0.01), however, between the Tongxinluo and model groups there were no significant differences in the levels of blood lipids. In the model group the blood level of ET was raised significantly and the level of NO was significantly decreased (both P < 0.01). The ET levels of the 2 intervention groups were both significantly lower than that of the model group (both P < 0.01), and the NO levels of the 2 intervention groups were both significantly higher than those of the normal group (P < 0.01 approximately 0.05), however, there were no significant differences in the ET and NO levels between these 2 intervention groups (all P > 0.05). Sclerotic plaques were distributed intensely at high degrees in the model group. The sclerotic changes of the 2 intervention groups were significantly milder. The contents of collagen of the 2 intervention groups were 0.11 +/- 0.08 and 0.22 +/- 0.11 respectively, both significantly higher then that of the model group (0.01 +/- 0.01, both P < 0.05). The intima/media ratios of aorta of the 2 intervention groups were 0.25 +/- 0.13 and 0.28 +/- 0.12 respectively, both significantly lower than that of the model group (0.60 +/- 0.37). The macrophage amount in the plaque (RAM-11 positively stained area) of the 2 intervention groups were 0.11 +/- 0.10 and 0.06 +/- 0.43 respectively, both significantly lower than that of the model group (0.24 +/- 0.14). The levels of protein expression of MMP-1 and COX-2 in the atherosclerotic lesions of the model group were both significantly higher than those of the normal group and the MMP-1 and COX-2 protein expression levels of the 2 intervention groups were all significantly lower than those of the model group (P < 0.05 approximately 0.01), however, there were no significant differences between these 2 groups (both P > 0.05). Significant linear correlation existed in the MMP-1 and COX-2 positively stained areas (r = 0.533, P = 0.007) and protein expression level (r = 0.833, P < 0.01). Compared with the normal group, the mRNA expression level of FasL in the aorta tissue of the model group was significantly higher (2.44 +/- 0.44) and the mRNA expression level of bcl was significantly lower (0.17 +/- 0.11). Compared with the model group, the mRNA expression levels of FasL of the 2 intervention groups were 0.47 +/- 0.36 and 1.32 +/- 0.61 respectively, both significantly lower and the mRNA expression levels of bcl were 0.64 +/- 0.16 and 1.66 +/- 0.94 respectively, both significantly higher (all P < 0.05 approximately 0.01), with the FasL mRNA expression of the Tongxinluo group significantly higher than that of the simvastatin group (P < 0.05).


CONCLUSIONS
Tongxinluo and simvastatin have the same effects of stabilizing the vulnerable plaques, and the mechanism may be related with inhibition of expression of COX-2 and MMP and reduction of the apoptosis in the atherosclerotic plaque.
Li
Zhen
Z
Center of Diagnosis and Treatment of Coronary Artery Disease, Fuwai Hospital, China Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
Yang
Yue-jin
YJ
Qin
Xue-wen
XW
Ruan
Ying-mao
YM
Chen
Xi
X
Meng
Liang
L
Zhang
Hui-dong
HD
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000627:therapeutic use*; D053222:Fas Ligand Protein / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D008517:Phytotherapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000008:administration & dosage / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004365:Drugs, Chinese Herbal; D053222:Fas Ligand Protein; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014280:Triglycerides; C513941:tongxinluo; D002784:Cholesterol; D019821:Simvastatin; D051546:Cyclooxygenase 2; D020781:Matrix Metalloproteinase 1