Pioglitazone preserves vein graft integrity in a rat aortic interposition model.
OBJECTIVE
Improvement of vein graft patency may be highly beneficial in coronary artery bypass grafting, but graft degeneration is considered to be one of the main pathophysiologic causes for vein graft failure. Because peroxisome proliferator-activated receptor-gamma activator pioglitazone was recently reported to possess pleiotropic protective effects on various organs and tissues, we conducted experiments to test the hypothesis that pioglitazone could prevent graft degeneration, leading to the preservation of vein graft integrity.


METHODS
In a rat aortic interposition model with autologous femoral vein, pioglitazone (3 mg/kg/d) or vehicle (normal saline) was given to rats by gastric gavage once per day beginning 3 days before surgery and ending 8 weeks after surgery. Vein graft degeneration and remodeling were assessed at 24 hours, 7 days, 8 weeks, and 6 months after surgery.


RESULTS
At 24 hours, pioglitazone significantly reduced endothelial desquamation, reactive oxygen species generation, myeloperoxidase activity, and lipid peroxidation in vein grafts. At 7 days, mRNA expression and gelatinolytic activity of matrix metalloproteinase-2 and 9 in vein grafts were significantly suppressed by pioglitazone treatment. Immunofluorescent staining showed that pioglitazone enhanced peroxisome proliferator-activated receptor-gamma expression in vein grafts at 8 weeks, especially in their intimal side. At 6 months, pioglitazone treatment prevented graft dilation (52.3% +/- 3.1% vs 90.7% +/- 9.9%, P = .0041) and neointimal hyperplasia (14.6% +/- 1.3% vs 29.9% +/- 2.9%, P = .0008), and increased graft flow velocity ratio (0.86 +/- 0.03 vs 0.59 +/- 0.04, P < .0001), compared with vehicle treatment.


CONCLUSIONS
Pioglitazone prevents graft degeneration under arterial pressure stress and preserves the vein graft integrity in a rat aortic interposition model.
Chen
Zhi
Z
Department of Surgery, Division of Cardiovascular Surgery, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
Hasegawa
Tomomi
T
Tanaka
Akiko
A
Okita
Yutaka
Y
Okada
Kenji
K
D000284:Administration, Oral; D000714:Anastomosis, Surgical; D000818:Animals; D001012:Aorta, Abdominal / Q000601:surgery*; D001783:Blood Flow Velocity; D004108:Dilatation, Pathologic; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005268:Femoral Vein / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D006085:Graft Survival / Q000187:drug effects*; D006965:Hyperplasia; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D023421:Models, Animal; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism; D014182:Transplantation, Autologous; D014654:Vascular Patency / Q000187:drug effects
D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D019714:Tissue Inhibitor of Metalloproteinases; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; D000077205:Pioglitazone