Differential effects of peroxisome proliferator activator receptor-alpha and gamma ligands on intimal hyperplasia after balloon catheter-induced vascular injury in Zucker rats

Abstract

Background: Patients with type 2 diabetes mellitus have a higher rate of restenosis following angioplasty. Peroxisome proliferator activator receptor-alpha (PPAR) and gamma ligands such as fenofibrate and rosiglitazone, respectively, have been shown to have protective effects on the vessel wall. We studied the effect of fenofibrate and rosiglitazone on intimal hyperplasia in the Zucker rat, a model for insulin resistance and type 2 diabetes mellitus, following balloon catheter-induced injury.

Methods and results: Three groups of 13-week-old female fatty Zucker rats were administered an aqueous suspension of either 3 mg/kg/d rosiglitazone (n=7) or 150 mg/kg/d fenofibrate (n=6) by gavage, or served as controls (n=9). In addition, two groups of 13-week-old female lean Zucker rats were either administered 3 mg/kg/d rosiglitazone (n=6) or served as controls (n=6). Carotid balloon injury was induced 1 week after the drugs were started. The drug administration was continued for 3 weeks. A 2-mm balloon catheter was introduced through the femoral artery to the left carotid. The balloon was inflated to 4 atmospheres for 20 seconds and then was deflated to 2 atmospheres and dragged down to the aorta. The rats were killed 3 weeks after the injury. The carotid intima/media ratio was calculated. Intimal hyperplasia after carotid balloon-induced injury in the fatty Zucker rats was significantly reduced in the group treated with rosiglitazone (0.18 +/- 0.29) compared with the untreated group (0.97 +/- 0.13; P<.01). Plasma glucose, triglyceride, and insulin levels were elevated, indicative of the presence of insulin resistance; rosiglitazone treatment significantly reduced insulin and triglyceride levels without decreasing glucose. Rosiglitazone treatment also reduced, but to a lesser extent, the intimal hyperplasia in the lean Zucker rats (0.57 +/- 0.10 vs 1.06 +/- 0.12 treated and untreated, respectively; P<.01); however, it had no effect on insulin, triglyceride, or glucose levels in this group. The intimal hyperplasia in the fatty Zucker rats treated with fenofibrate was not reduced compared with controls (0.84 +/- 0.26 vs 0.97 +/- 0.13, respectively); fenofibrate reduced insulin and triglyceride, but not glucose levels, in these animals.

Conclusions: The PPAR-gamma ligand rosiglitazone, but not the PPAR-alpha ligand fenofibrate, decreases intimal hyperplasia following balloon injury in both fatty and lean Zucker rats. This effect of the PPAR-gamma ligand was independent of glycemia, insulin, and lipid levels, and was more pronounced in insulin-resistant rats.