Wild-type p53 gene transfer inhibits neointima formation in human saphenous vein by modulation of smooth muscle cell migration and induction of apoptosis.
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) to 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.
George
S J
SJ
Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol, BS2 8HW, UK.
Angelini
G D
GD
Capogrossi
M C
MC
Baker
A H
AH
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D001026:Coronary Artery Bypass; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009924:Organ Culture Techniques; D012501:Saphenous Vein / Q000166:cytology* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D017539:Tunica Intima / Q000166:cytology*; D014654:Vascular Patency
D016159:Tumor Suppressor Protein p53