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(Circulation. 2001;103:2980.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Effects of Balloon Injury on Neointimal Hyperplasia in Streptozotocin-Induced Diabetes and in Hyperinsulinemic Nondiabetic Pancreatic Islet–Transplanted Rats

Ciro Indolfi, MD; Daniele Torella, MD; Luigi Cavuto, MD; Alberto M. Davalli, MD; Carmela Coppola, MD; Giovanni Esposito, MD; Mariolina V. Carriero, MD; Antonio Rapacciuolo, MD; Emilio Di Lorenzo, MD; Eugenio Stabile, MD; Cinzia Perrino, MD; Alaide Chieffo, MD; Francesco Pardo, MD; Massimo Chiariello, MD

From the Division of Cardiology (D.T., L.C., C.C., A.R., E.D., E.S., C.P., A.C., M.C.) and the Division of Internal Medicine (F.P.), University Federico II, and the National Cancer Institute (M.V.C.), Naples; Magna Graecia University, Catanzaro (C.I.); and the Unit of Metabolic Disease, Istituto Scientifico San Raffaele, Milan (A.D.), Italy; and the Department of Medicine, Duke University, Durham, NC (G.E.). The first 2 authors contributed equally to this study.

Correspondence to Ciro Indolfi, MD, FACC, FESC, Laboratory of Clinical and Experimental Interventional Cardiology, Federico II University, Via Sergio Pansini, 5, 80131 Naples, Italy. E-mail indolfi{at}unina.it

Background—The mechanisms of increased neointimal hyperplasia after coronary interventions in diabetic patients are still unknown.

Methods and Results—Glucose and insulin effects on in vitro vascular smooth muscle cell (VSMC) proliferation and migration were assessed. The effect of balloon injury on neointimal hyperplasia was studied in streptozotocin-induced diabetic rats with or without adjunct insulin therapy. To study the effect of balloon injury in nondiabetic rats with hyperinsulinemia, pancreatic islets were transplanted under the kidney capsule in normal rats. Glucose did not increase VSMC proliferation and migration in vitro. In contrast, insulin induced a significant increase in VSMC proliferation and migration in cell cultures. Furthermore, in VSMC culture, insulin increased MAPK activation. A reduction in neointimal hyperplasia was consistently documented after vascular injury in hyperglycemic streptozotocin-induced diabetic rats. Insulin therapy significantly increased neointimal hyperplasia in these rats. This effect of hyperinsulinemia was totally abolished by transfection on the arterial wall of the N17H-ras–negative mutant gene. Finally, after experimental balloon angioplasty in hyperinsulinemic nondiabetic islet-transplanted rats, a significant increase in neointimal hyperplasia was observed.

Conclusions—In rats with streptozotocin-induced diabetes, balloon injury was not associated with an increase in neointimal formation. Exogenous insulin administration in diabetic rats and islet transplantation in nondiabetic rats increased both blood insulin levels and neointimal hyperplasia after balloon injury. Hyperinsulinemia through activation of the ras/MAPK pathway, rather than hyperglycemia per se, seems to be of crucial importance in determining the exaggerated neointimal hyperplasia after balloon angioplasty in diabetic animals.

Key Words: diabetes mellitus • balloon • angioplasty • insulin

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