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

Abstract

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.

Receptor for AGE (RAGE) Mediates Neointimal Formation in Response to Arterial Injury

“…24,25 Balloon injury activates the MAPK pathway in diabetics, and hyperinsulinemia activation of the MAPK pathway has been shown to be of importance in the exaggerated neointimal hyperplasia after balloon injury in diabetic animals. 26 Blockade of RAGE/ ligand interaction decreases MAPK activity in cultured SMCs in a concentration-dependent manner. 27 Inhibition of RAGE/ ligand interaction decreased tumor cell proliferation and invasion by suppressing the activation of p44/p42, p38, and SAP/JNK MAP Kinases pathways.…”

NO Attenuates Insulin Signaling and Motility in Aortic Smooth Muscle Cells via Protein Tyrosine Phosphatase 1B–Mediated Mechanism

“…This notion is based on recent studies indicating that neointimal enlargement may be dependent on elevated insulin rather than elevated glucose levels. 2,3 Interestingly, one of these studies 3 found that hyperinsulinemia without diabetes also resulted in enhanced neointima formation after vascular injury, a finding that underscores the pivotal role of elevated insulin as a vascular pathogen. Other studies have reported that diabetes may be associated with NO deficiency, 16 a finding that could explain the tendency of insulin to enhance neointimal formation in vascular disease.…”

“…Insulin stimulated the motility of aortic smooth muscle cells by Ϸ3-fold, confirming a recent report. 3 Conversely, the NO donor SNAP attenuated the capacity of insulin to stimulate cell motility by Ͼ80% (please see online Figure I, which can be accessed at http://atvb.ahajournals.org).…”

“…4 -7 Similar to many other growth factors, insulin has the capacity to stimulate cell motility in vitro, which could explain the pathogenesis of diabetic neointimal growth. 3,8 Early studies from several laboratories, including ours, have reported that NO decreases vascular smooth muscle cell proliferation in subcultured cells from adult rats or in primary cultures from newborn rats. 9,10 More recent studies have reported that NO also inhibits aortic smooth muscle cell motility.…”

“…1 Most forms of vascular disease in conduit arteries manifest neointimal enlargement, and although type II diabetes is associated with hyperglycemia as well as hyperinsulinemia, recent studies have suggested that elevated insulin levels may be the more important factor in the pathogenesis of neointimal enlargement. 2,3 The proliferation and motility of vascular smooth muscle cells is regulated in reciprocal fashion by stimulators (eg, fibroblast growth factor, platelet-derived growth factor, and heparin-binding epidermal growth factor) and inhibitors of mitogenesis or motility (eg, prostanoids, heparin, atrial natriuretic factor, and transforming growth factor-␤). 4 -7 Similar to many other growth factors, insulin has the capacity to stimulate cell motility in vitro, which could explain the pathogenesis of diabetic neointimal growth.…”