Wild-type p53 gene transfer inhibits neointima formation in human saphenous vein by modulation of smooth muscle cell migration and induction of apoptosis

被引:68
作者
George, SJ [1 ]
Angelini, GD
Capogrossi, MC
Baker, AH
机构
[1] Univ Bristol, Bristol Royal Infirm, Bristol Heart Inst, Bristol BS2 8HW, Avon, England
[2] Ist Ricovero & Cura Carattere Sci, Ist Dermopat Immacolata, Lab Patol Vascolare, Rome, Italy
基金
英国医学研究理事会;
关键词
gene therapy; vein graft; p53; adenovirus; smooth muscle cell;
D O I
10.1038/sj.gt.3301431
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Patency of autologous human saphenous vein coronary artery bypass grafts (CABG) is compromised by intimal thickening and superimposed atherosclerosis, caused by migration of vascular smooth muscle cells (SMC) ic? the intima where they proliferate. Here, using adenoviral transfer, we have targeted SMCs using wild-type p53 (wt p53) overexpression. initial in vitro analyses demonstrated that wt p53 overexpression had no effect on SMC proliferation but promoted apoptosis, which was inhibited by co-expression of bcl2 or crmA. Wt p53 inhibited SMC invasion through reconstituted matrices, a phenotype not affected by bcl2 or crmA. Overexpression of wt p53 in human saphenous vein before organ culture significantly induced apoptosis (P < 0.01, Student's t test) without affecting proliferation rates either in the media or in the intima. SMC migration was, however. significantly reduced by wt p53 (P < 0.01. Student's t test). intimal thickening and the number of neointimal cells were reduced by 89% and 73%, respectively, after 14 days (P < 0.01 and P < 0.001, respectively Student's t test). This study demonstrates that overexpression of wt p53 promotes apoptosis and inhibits migration of SMC leading to reduced intimal thickening. This maybe a useful approach for increasing patency rates in CABG procedures in the clinic.
引用
收藏
页码:668 / 676
页数:9
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