Pioglitazone prevents intimal hyperplasia in experimental rabbit vein grafts

摘要

Background: Intimal hyperplasia is a major obstacle to patency after vein grafting. Several clinical trials revealed that pioglitazone, a peroxisome proliferator-activated receptor-γ ligand, exerts beneficial actions on cardiovascular complications. We investigated whether pioglitazone modulates intimal hyperplasia in experimental rabbit autologous vein grafts. Methods: Male Japanese White rabbits were randomly divided into two groups: one group received pioglitazone as food admixture at a concentration of 0.01%, and the other did not (control). One week later, each group underwent reversed autologous vein bypass grafting of the right common carotid artery using ipsilateral external jugular vein. Pioglitazone therapy was continued after surgery and until harvest. Intimal hyperplasia of the grafted vein was assessed at 28 days. Two weeks after implantation, proliferative cells in the neointima were identified by immunohistochemical staining with Ki-67 monoclonal antibody. To determine apoptotic cells, we performed terminal deoxynucleotidyl transferase-mediated deoxyuride-5′-triphosphate nick-end labeling (TUNEL) staining. Blood samples were collected at 28 days after implantation for measuring metabolic parameters such as plasma glucose and total cholesterol. Adiponectin levels were determined by Western blot analysis. Finally, we assessed adiponectin-related signaling pathway, 5′ adenosine monophosphate-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK) in the grafted vein by Western blot analysis. Results: Treatment with pioglitazone markedly inhibited intimal hyperplasia of carotid interposition-reversed jugular vein grafts in the pioglitazone group (0.54 ± 0.04 mm 2) vs control (0.93 ± 0.04 mm 2; n = 7; P .01). Pioglitazone treatment reduced the number of Ki-67-positive proliferating cells in the neointima of the vein grafts at 14 days after implantation in the pioglitazone group (4.1% ± 1.1%) vs the controls (16.8% ± 1.7%; P .05). The frequency of TUNEL-positive apoptotic cells was enhanced by pioglitazone (3.5% ± 0.5%) vs the controls (1.2% ± 0.1%; P .05). Pioglitazone treatment also increased plasma levels of adiponectin, a vascular protective hormone, and led to an increase in phosphorylation of AMPK and a decrease in phosphorylation of ERK in the grafted vein. Conclusions: Pioglitazone attenuates intimal hyperplasia of the vein graft after autologous bypass grafting by its ability to suppress cell proliferation and enhance apoptosis. Pioglitazone could represent a therapeutic target for the prevention of graft failure after bypass grafting.