[Induction of atherosclerotic plaque instability in rabbits after transfection of human wild-type p53 gene].
OBJECTIVE
To develop an animal model of unstable atherosclerotic plaques.


METHODS
Sixty-four New Zealand white rabbits were randomly divided into two groups: group A (n = 54, undergoing balloon-induced abdominal aortic wall injury and then fed on a diet of 1% cholesterol) and group B (n = 10, fed on a diet of 1% cholesterol only). At the end of the eighth week, the rabbits in group A were randomly divided into two subgroups: group A1 (n = 27) and group A2 (n = 27). Recombinant adenovirus carrying human wild-type p53 gene and beta galactosidase (LacZ) genes were injected through a catheter into the aortic segments rich in plaques in group A1 and A2 respectively. Two weeks later, 10 rabbits each in group A1 and A2 were killed to observe the occurrence rate of spontaneous plaque rupture, and the remaining rabbits in group A1, A2 and B all underwent pharmacological triggering by Chinese Russell's viper venom injected subperitoneally and histamine injected intravenously two times with an interval of 24 hours. Twenty-four hours after the second pharmacological triggering the remaining rabbits were all killed and their abdominal aortae were taken out to undergo macropathologic observation, staining, and immunohistochemistry to examine the accumulation of macrophages and the expression of p53 protein, in the plaques with and without rupture respectively. At the beginning of the experiment and before being killed the serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein choloesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were examined.


RESULTS
Before the rabbits were killed the blood-lipid levels were significantly increased in comparison with the baseline levels (all P < 0.01), however, without significant differences among the three groups. The rate of cells positive in p53 transfection was 32.4% +/- 10.2% in the group A1, significantly higher than those in the group A2 and group B (15.8% +/- 3.6% and 16.2% +/- 6.7% respectively, both P < 0.001). The fibrous cap of the plaque was significantly thinner in the group A1 than in the other 2 groups (both P < 0.05). The apoptosis rate was 2.5% +/- 0.8% in the group A1, significantly higher than those in the group A2 and group B (1.0% +/- 0.3% and 0.9% +/- 0.4% respective, both P < 0.01). The accumulation of macrophages within the plaques was significantly remarkable and the number of vessel smooth muscle cells was much smaller in the group A1. Plaque rupture and thrombosis occurred in 12 rabbits, numbering 20 lesions, after pharmacological triggering in the group A1, and occurred in only 5 rabbits, numbering 7 lesions, in the group A2. None of the rabbits in group B showed any lesions after the pharmacological triggering.


CONCLUSIONS
With transfection of human wild-type p53 genes and pharmacological triggering, plaque rupture and thrombosis may occur in most atherosclerotic lesions in rabbits, which offered a reliable model for the further study of unstable plaques.
Chen
Wen-qiang
WQ
Department of Cardiology, Qilu Hospital, Shandong University, Jinan 250012, China.
Zhang
Yun
Y
Zhang
Mei
M
Ji
Xiao-ping
XP
Lin
Chen
C
Zhu
Yong-feng
YF
Zhang
Wei
W
Wang
Rong
R
Liu
Yan
Y
Yao
Gui-hua
GH
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000737:chemistry; D008297:Male; D011817:Rabbits; D011897:Random Allocation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013927:Thrombosis / Q000209:etiology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014757:Viper Venoms / Q000494:pharmacology; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D014757:Viper Venoms; D002784:Cholesterol; D001616:beta-Galactosidase