Effect Of Rosiglitazone On Restenosis Of Injured Rats Aorta And Study On Its Molecular Mechanisms

Objective: Percutaneous transluminal coronary angioplasty (PTCA) has made the treatment of coronary artery disease step into a new period. About 30 percent to 50 percent incidence of restenosis after PTCA is the vital limitation for its long term effect. People try to find a new method in order to prevent restenosis. Peroxisome proliferator activated receptor gamma (PPAR- γ) is a transcription factor belonging to the nuclear hormone receptor gene superfamily. Thiazolidinediones (TZDs) are synthetic ligands for PPAR-γ. Rosiglitazone and Pioglitazone belong to TZDs.They have been used extensively as insulin-sensitizer in the treatment of type 2 diabetes.In recent years it has been established that TZDs can inhibit inflammation and vascular smooth muscle cell (VSMC) migration and proliferation. The migration and proliferation of VSMC is the key pathology process, one of the mechanisms required for VSMC migration is the degradation of extracellular matrix , the matrix metalloproteinases (MMPs), especially matrix metalloproteinase-9(MMP-9), play an important role. Studies have showed that cytokines were involved in neointimal formation. Troglitazone, a ligand of PPAR- y ,can inhibit the MMP-9 expression of VSMC and level of macrophage TNF- αin vitro.In this study ,by using the model which was established by injuring the rat aorta endothelium with balloon catheter we could investigated the effect of Rosiglitazone on TNF- a level of plasma and MMP-9 expression in vessel wall.Methods: The restenosis model was established by injuring the rat aorta endothelium with balloon catheter. 90 SD rats were divided into three groups.Namely Rosiglitazone group,controul group and angioplasty group.Six SD rats were killed before endithetial injury, 4h, ID, 7D after endothelium injury respectively. The plasma TNF- a level were detected with radioimmunoassay. Pathological changes of the injured aortic endothelium were assessed with HE. The mRNA and protein expression of MMP-9 were respectively detected with in situ hybridization and the immunohistochemistry.The results of experiments were indicated with (M±SD) .The one -way ANOVA was carried out for ststistics evaluation by SAS v6.12 . Significance was set at P<0.05.Results: 1. Compared with smooth intima and orderly arranged medial VSMC of aorta in the control group rats. On day 14 after endothelium, progressive and widespread intima thickening and lumen stenosis were observed. Rosiglitazone could decrease the intima proliferation and lumen restenosis compared with Angioplasty group. The intima area was higher in Angioplasty group than in the control groupCPO.OSXbut The lumen area was smaller in Angioplasty group than in the control group (PO.05) ;Compared with Angioplasty group, The intimaarea was smaller in Rosiglitazone group (/*<().05) ,but The lumen area was larger than Angioplasty group (PO.05) . 2. In our study, the level of plasma TNF- a had ambulatory change. Before endothelium injury, the level of plasma TNF- a had no change within three groups (P>0.05).On hour 4 after endothelium injury, the level of plasma TNF- a was increasingly higher in Angioplasty group than in Control groupC/'O.Ol) and also was higher than in Rosiglitazone group(P<0.05) . However, On day 1 and 7 the level of plasma TNF- a was almost in normal level compared with control group (P >0.05). 3. On day 7 after endothelial injury the expression mRNA and protein of MMP-9 was remarkably high in intima and VSMC in Angioplasty group compared with Control group and Rosiglitazone group ,the difference was significant (P <0.05),and no remarkably difference was shown between Control group and Rosiglizatone group^ >0.05 ). However, on day 14 the expression of MMP-9 mRNA and protein of Angioplasty group was remarkably low and had no difference compared with Control group (P >0.05). 4. Compared with control group, the plasma glucose and ALT level had no difference (P>0.05).Conclusions: 1. The rat vascular restenosis model after endothelium injury has successfully been established. 2. TNF- a is involved in the pathological process restenosis, Rosiglizatone could inhibit the level of plasma TNF- a and decrease the inflammation reaction after endothelial injury. 3. The mRNA...