Overexpression of p53 increases lumen size and blocks neointima formation in porcine interposition vein grafts.
Patency rates for autologous saphenous vein (SV) conduits used in coronary artery bypass grafts remain poor. Patients with failed grafts are difficult to treat with subsequent interventions, necessitating the development of innovative therapies. Previous studies have suggested that induction of smooth muscle cell (SMC) apoptosis may reduce neointima formation. We overexpressed the proapoptotic gene p53 at the lumenal surface of SV grafts using adenoviral (Ad)-mediated gene transfer in porcine SVs prior to grafting in vivo and analyzed at 7 and 28 days (n = 6 and 7 per group, respectively). p53 overexpression induced a significant upregulation in apoptosis (4 +/- 0.6% for Adp53-infected grafts vs 0.6 +/- 0.1% for Adbeta-gal-infected grafts) and reduced neointimal proliferation by 28 +/- 1% at day 7 postinfection. Adp53-infected grafts had significantly greater lumenal areas than controls at both time points (4.8 +/- 0.6 mm2 vs 2.9 +/- 0.5 mm2 and 10.0 +/- 2.5 mm2 vs 4.2 +/- 1.2 mm2 at 7 and 28 days, respectively). Total graft areas were also increased at 28 days by p53, indicating positive vessel remodeling. Additionally, the thickening of the neointima was significantly reduced by 68 +/- 22% and 28 +/- 3% by p53 overexpression at day 7 and 28, respectively. Importantly, phenotypic changes were maintained at 3 months. Induction of SMC apoptosis by transient p53 overexpression positively influenced vein graft remodeling.
Wan
Song
S
Division of Cardiothoracic Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong.
George
Sarah J
SJ
Nicklin
Stuart A
SA
Yim
Anthony P C
AP
Baker
Andrew H
AH
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001026:Coronary Artery Bypass / Q000379:methods*; D015316:Genetic Therapy; D006083:Graft Occlusion, Vascular / Q000473:pathology / Q000517:prevention & control*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis / Q000378:metabolism; D012501:Saphenous Vein / Q000473:pathology / Q000637:transplantation; D013552:Swine; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D017539:Tunica Intima / Q000473:pathology*; D015854:Up-Regulation; D001616:beta-Galactosidase / Q000032:analysis
D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; D001616:beta-Galactosidase