Rosiglitazone Reduces the Accelerated Neointima Formation After Arterial Injury in a Mouse Injury Model of Type 2 Diabetes

Abstract

Background-Hyperglycemia (HG) and hyperinsulinemia (HI) may be factors enhancing the atherosclerotic complications of diabetes. We hypothesized that specific feeding of C57BL/6 apolipoprotein (apo) E Ϫ/Ϫ mice would alter their metabolic profiles and result in different degrees of neointima (NI) formation. We additionally hypothesized that an insulin-sensitizing agent (rosiglitazone) would prevent the development of type 2 diabetes and reduce neointima formation after carotid wire injury measured at 28 days. Methods and Results-Fasting glucose and insulin levels were elevated in the Western diet (WD) group, with a trend toward higher insulin levels and euglycemia in the fructose diet (FD)-fed mice. NI formation was exaggerated in the WD group compared with the FD or chow control groups. In the WD mice given rosiglitazone, glucose and insulin levels remained normal and NI formation was significantly reduced, as was NI macrophage content. Conclusions-These findings demonstrate that apoEϪ/Ϫ mice fed a WD develop type 2 diabetes with an exaggerated NI response to injury. FD mice maintain euglycemia but develop insulin resistance, with an intermediate degree of NI growth compared with chow diet controls. Rosiglitazone prevents the development of hyperglycemia and hyperinsulinemia and normalizes the insulin release profile in the apoE Ϫ/Ϫ , WD-fed mouse and significantly reduces NI formation by 65% after carotid wire injury while reducing macrophage infiltration. These data support the hypothesis that type 2 diabetes in the setting of elevated cholesterol accelerates the response to vascular injury and suggest that agents that improve insulin sensitivity may have therapeutic value in reducing restenosis in type 2 diabetes.

CD40 Ligand Promotes Mac-1 Expression, Leukocyte Recruitment, and Neointima Formation after Vascular Injury

“…We and others have previously reported that atherosclerosisprone apoE-deficient (apoE Ϫ/Ϫ ) mice develop severe hypercholesterolemia, accelerated atherosclerosis, significant insulin resistance, and hyperglycemia when fed an atherogenic Western diet (WD). [17][18][19] The present study further showed that WD-fed apoE Ϫ/Ϫ mice developed high levels of plasma sCD40L as well as exaggerated neointima formation after carotid wire denudation injury compared with chow-fed apoE Ϫ/Ϫ mice. Therefore, this model provides a unique opportunity for understanding the role of elevated circulating CD40L in neointima formation after vascular injury under clinically relevant conditions.…”

RAGE Axis

“…Macrophage infiltration into the expanding neointima was also reduced by this intervention. 52 Note that these studies are in contradistinction to those of Levi et al 39 with respect to the effect of rosiglitazone on hyperglycemia. Specifically, in Levi's studies, apo EϪ/Ϫ mice were made frankly diabetic by relative deficiency of insulin using streptozotocin; 39 in the Phillips studies, hyperglycemia was induced by feeding Western diet, thereby causing insulin resistance.…”

“…Phillips et al used Western diet-fed apo EϪ/Ϫ mice to show that these mice develop insulin-resistant diabetes; administration of rosiglitazone prevented the development of hyperglycemia and hyperinsulinemia. 52 In parallel, neointimal expansion was reduced by 65% after arterial injury in Peroxisome proliferator-activated gamma agonist (rosiglitazone) versus vehicle-fed apo EϪ/Ϫ mice. Macrophage infiltration into the expanding neointima was also reduced by this intervention.…”

Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis

“…ApoE KO mice fed a WD exhibit a metabolic phenotype consistent with T2D, which includes elevated insulin and glucose levels as compared with standard chow-fed mice (28)(29)(30). During the 12-week time period, mice were injected intraperitoneally every 3 days with either vehicle peptide or CavNOxin (2.5 mg/kg).…”