Intraplaque injection of Ad5-CMV.p53 aggravates local  inflammation and leads to plaque instability in rabbits.
This study aims to develop a new animal model of vulnerable plaques and investigate the potential mechanisms of exogenous p53-induced plaque instability. Forty rabbits underwent aortic balloon injury, were fed a 1% cholesterol diet for 10 weeks and then normal chow for 6 weeks. Rabbits were divided into Ad5-CMV.p53-treated group (n = 16), Ad5-CMV.lac Z-treated group (n = 16) and blank control group (n = 8). Under the guidance of intravascular ultrasound, a 50-microl suspension of adenovirus containing p53 or lac Z was injected into the largest plaque of the first two groups, respectively, and these rabbits received pharmacological triggering 2 weeks later. In 76.9% of rabbits with p53 transfection, plaque rupture was found, which was significantly (P < 0.05) higher than that in the Ad5-CMV.lac Z-treated plaques (23.1%), or blank controls plaques (0%). Increased apoptotic cells, and subsequently, decreased vascular smooth muscle cells and collagen content, enhanced intima macrophage accumulation, increased C-reactive protein (CRP) and matrix metalloproteinases staining and high serum levels of high sensitive CRP (hs-CRP) and monocyte chemoattractant protein-1 (MCP-1) were observed in Ad5-CMV.p53-treated rabbits. However, a binary logistic regression model revealed that hs-CRP concentration rather than apoptosis rate played an independent role in plaque rupture with an odds ratio as 1.314 (95% CI: 1.041-1.657, P = 0.021), and there were high positive correlations between inflammatory biomarkers (hs-CRP or MCP-1) and apoptosis (R(2) = 0.761, and R(2) = 0.557, respectively, both P < 0.01). Intraplaque injection of p53 gene provides a safe and effective method for inducing plaque vulnerability in rabbits. The destabilizing effect of p53 overexpression is mediated mainly through apoptosis-enhanced inflammation rather than cell apoptosis itself.
Zhang
Lei
L
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong, P.R. China.
Liu
Yan
Y
Department of Traditional Chinese Medicine, Shandong University Qilu Hospital, Jinan, Shandong, P.R. China.
Lu
Xiao Ting
XT
Department of Traditional Chinese Medicine, Shandong University Qilu Hospital, Jinan, Shandong, P.R. China.
Xu
Xin Sheng
XS
Department of Cardiology, Dongying People's Hspital, Shandong, P.R. China.
Zhao
Yu Xia
YX
Department of Traditional Chinese Medicine, Shandong University Qilu Hospital, Jinan, Shandong, P.R. China.
Ji
Xiao Ping
XP
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong, P.R. China.
Zhang
Peng Fei
PF
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong, P.R. China.
Liu
Chun Xi
CX
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong, P.R. China.
Tang
Meng Xiong
MX
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong, P.R. China.
Chen
Wen Qiang
WQ
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong, P.R. China.
Zhang
Yun
Y
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong, P.R. China.
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D050197:Atherosclerosis / Q000473:pathology*; D003587:Cytomegalovirus / Q000235:genetics*; D016158:Genes, p53; D005822:Genetic Vectors; D007150:Immunohistochemistry; D007249:Inflammation / Q000209:etiology*; D008297:Male; D011817:Rabbits