Diabetes Accelerates Smooth Muscle Accumulation in Lesions of Atherosclerosis

Abstract

In combination with other factors, hyperglycemia may cause the accelerated progression of atherosclerosis in people with diabetes. Arterial smooth muscle cell (SMC) proliferation and accumulation contribute to formation of advanced atherosclerotic lesions. Therefore, we investigated the effects of hyperglycemia on SMC proliferation and accumulation in vivo and in isolated arteries and SMCs by taking advantage of a new porcine model of diabetes-accelerated atherosclerosis, in which diabetic animals are hyperglycemic without receiving exogenous insulin. We show that diabetic animals fed a cholesterol-rich diet, like humans, develop severe lesions of atherosclerosis characterized by SMC accumulation and proliferation, whereas lesions in nondiabetic animals contain fewer SMCs after 20 weeks. However, high glucose (25 mmol/l) does not directly stimulate the proliferation of SMCs in isolated arterial tissue from diabetic or nondiabetic animals, or of cultured SMCs from these animals or from humans. Furthermore, the mitogenic actions of platelet-derived growth factor, IGF-I, or serum are not enhanced by high glucose. High glucose increases SMC glucose metabolism through the citric acid cycle and the pentose phosphate pathway by 240 and 90%, respectively, but <10% of consumed glucose is metabolized through these pathways. Instead, most of the consumed glucose is converted into lactate and secreted by the SMCs. Thus, diabetes markedly accelerates SMC proliferation and accumulation in atherosclerotic lesions. The stimulatory effect of diabetes on SMCs is likely to be mediated by effects secondary to the hyperglycemic state. Diabetes 50:851-860, 2001 I t is estimated that 75-80% of adults with diabetes die from complications of atherosclerosis. The progression of atherosclerotic lesions is accelerated by diabetes (1). Thus, stroke, coronary heart disease, and peripheral arterial disease are more common and occur at an earlier age in diabetic people than in the general population (1-2).The cellular mechanisms underlying the accelerated progression of atherosclerotic lesions in diabetic arteries are still largely unknown. Hyperinsulinemia, lipid abnormalities, and hyperglycemia have each been suggested to cause this response. Because smooth muscle cell (SMC) proliferation and accumulation are key events in the development of advanced lesions, a number of studies have investigated the regulation of SMC proliferation. Studies on the effects of hyperinsulinemia show that direct mitogenic effects of insulin on SMCs are weak and that the principal mitogenic response elicited by insulin is mediated through a cross-reaction at high unphysiological insulin concentrations with the IGF-I receptor (3-6). Thus, a direct mitogenic action of hyperinsulinemia on SMCs in vivo is unlikely.It is becoming increasingly clear that many of the complications of diabetes arise from hyperglycemia that cannot be completely prevented using the methods of blood glucose control available today. This is particularly apparent for retinopathy, nephropathy,...

Contribution of Aldose Reductase to Diabetic Hyperproliferation of Vascular Smooth Muscle Cells

“…Although previous reports demonstrated increased intimal thickening after balloon injury in alloxaninduced diabetic rabbits (27) and BB Wistar diabetic rats (28), recent studies report exaggerated intimal expansion in obese Zucker rats (29) but not in rats with STZ-induced diabetes (29,30). Coupled with the observation that in some studies, high glucose failed to stimulate SMC proliferation in culture (31,32), it is currently believed that hyperglycemia per se does not stimulate intimal hyperplasia in injured vessels and that insulin resistance or hyperinsulineima is responsible for the increased propensity of human diabetic patients for restenosis. This view is further reinforced by studies (33,34) showing that although rigorous control of hyperglycemia significantly decreases the microvascular complications such as nephropathy and retinopathy, it does not affect macrovascular complications of diabetes.…”

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

“…Moreover, it is well established that subculture of the aortic smooth muscle cells reduces protein kinase G levels after a few subcultures, thus necessitating the use of primary or early subculture cells. 35 (2) Neointimal cells that are generated in vascular disease manifest a partially dedifferen- . Dominant-negative PTP1B mutant, C215S-PTP1B, blocks the capacity of NO donor SNAP to decrease insulinstimulated Erk phosphorylation.…”

“…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.…”

“…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.…”

Phenotype-specific inhibition of the vascular smooth muscle cell cycle by high glucose treatment

“…In vivo studies examining the proliferative response of medial and intimal cells in carotid arteries after balloon injury in rat models of type 1 and type 2 diabetes showed increased cell proliferation in type 2 diabetic obese Zucker rats, but not in streptozotocin-induced type 1 diabetic rats [15]. In a porcine model of diabetes-accelerated atherosclerosis, diabetes was shown to accelerate smooth muscle cell accumulation in atherosclerotic lesions, but glucose treatment did not have direct growth-promoting effects [16]. These data suggest that hyperglycaemia alone does not stimulate arterial cell proliferation.…”