Insulin stimulates arterial neointima formation in normal rats after balloon injury

Foster, Estrella; Zhang, Sui; Kahn, Andrew

doi:10.1111/j.1463-1326.2005.00513.x

Cited by 18 publications

(14 citation statements)

References 16 publications

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“…The rats were divided into 6 groups: (1) rats with blank implants and access to tap water (control = C); (2) rats with insulin implant (5 U/day) and access to glucose in their drinking water as a 40% (w/v) solution [insulin (5 U/day) + 40% oral glucose = I5G] as in Kim et al [9] but with i.p. glucose infusion (25%) to avoid any glucose lowering; (3) rats with insulin implant (4 U/day, which is similar to ∼3.9 U/day used in Foster et al [16]) and access to glucose in their drinking water as a 40% (w/v) solution [insulin (4 U/day) + 40% oral glucose = I4G]; (4) rats with insulin implant (4 U/day) and access to sucrose in their drinking water as a 10% (w/v) solution as in Foster et al [16] [insulin (4 U/day) + 10% oral sucrose = I4S]; (5) rats with blank implants and access to glucose in their drinking water as a 40% (w/v) solution (control glucose = CG), and (6) rats with blank implants and access to sucrose in their drinking water as 10% (w/v) solution (control sucrose = CS). The rats were fed a normal-fat diet, consisting of 12% fat in calories as used in Kim et al [9].…”

Section: Methodsmentioning

confidence: 99%

“…We have also determined the effect of oral glucose, without insulin treatment, on neointimal growth after arterial injury. In addition, we wished to investigate the effect of oral sucrose alone and in combination with insulin, as a recently published study found that neointimal growth was actually increased in insulin-treated rats after balloon catheter injury while normoglycemia was maintained with 10% oral sucrose [16], instead of the 40% glucose in water used in our studies where insulin had a protective effect. Sucrose contains fructose, which is a known inducer of insulin resistance [17], thus we speculate that sucrose alone (the effect of which was not evaluated in the previous study) may increase neointimal growth.…”

Section: Introductionmentioning

confidence: 99%

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Insulin Inhibits and Oral Sucrose Increases Neointimal Growth after Arterial Injury in Rats

Breen

Dhaliwall²,

Chan³

et al. 2010

J Vasc Res

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Background/Aims: In our previous studies, rats on insulin treatment (5 U/day) and oral glucose to avoid hypoglycemia had reduced neointimal growth after arterial injury. However, plasma glucose in the insulin-treated rats was lower than normal and the effect of oral glucose remained undetermined. In this study, the effects of normoglycemic hyperinsulinemia and oral glucose or sucrose were investigated in the same model. Methods: Rats were divided into 6 groups: (1) control implants and tap water; (2) insulin implants (5 U/day) and oral glucose + i.p. glucose to avoid any glucose lowering; (3) insulin implants (4 U/day) and oral glucose; (4) insulin implants (4 U/day) and oral sucrose; (5) control implants and oral glucose, and (6) control implants and oral sucrose. Results: Insulin treatment at both doses reduced neointimal area (p < 0.001) 14 days after injury in rats receiving oral glucose but not in those receiving oral sucrose. Oral glucose, without insulin, had no effect on neointimal formation, whereas oral sucrose increased neointimal growth (p < 0.05). Oral sucrose (p < 0.05) but not oral glucose decreased insulin sensitivity measured with hyperinsulinemic clamps. Conclusions: (1) Insulin decreases neointimal growth after arterial injury independent of glucose-lowering or oral glucose administration and (2) oral sucrose per se affects neointimal growth.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Insulin Inhibits and Oral Sucrose Increases Neointimal Growth after Arterial Injury in Rats

Breen

Dhaliwall²,

Chan³

et al. 2010

J Vasc Res

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“…Several studies (11,20,28,39) have reported that, in at least some strains of rats, hyperinsulinemia induces a significant increase of neointima formation. Thus, an aim of our study was to verify this finding in our model.…”

Section: Infusion Of Insulin Induced Modest Hyperinsulinemia But Notmentioning

confidence: 99%

“…It is now well accepted that metabolic syndrome and type 2 diabetes are strongly associated with adverse cardiovascular events in humans, although the underlying reasons for these associations have not been clarified (3,12,44,49,55). Several recent studies have reported that hyperinsulinemia is associated with vascular remodeling and enhanced neointima formation in models of experimental vascular injury as well as in humans (20,28,37,39,55). Moreover, hyperinsulinemia, but not hyperglycemia, has been reported to induce enhanced neointima formation in models of rat vascular injury (11, 28).…”

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confidence: 99%

Chronic insulin treatment suppresses PTP1B function, induces increased PDGF signaling, and amplifies neointima formation in the balloon-injured rat artery

Chang²,

Zhang³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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. Chronic insulin treatment suppresses PTP1B function, induces increased PDGF signaling, and amplifies neointima formation in the balloon-injured rat artery. Am J Physiol Heart Circ Physiol 296: H132-H139, 2009. First published November 14, 2008 doi:10.1152/ajpheart.00370.2008.-We tested the hypothesis that hyperinsulinemia induces the suppression of protein tyrosine phosphatase 1B (PTP1B) function, leading to enhanced PDGF receptor (PDGFR) signaling and neointimal hyperplasia. Rats were implanted with insulin-releasing pellets or sham pellets. Blood glucose levels, insulin levels, food and water intake, body weights, and blood pressures were measured. Neointimal hyperplasia was assessed by computerized morphometry 14 days after carotid balloon injury. PTP1B protein expression in injured arteries was determined via Western blot analysis, whereas PTP1B activity was determined via an immunophosphatase assay. Serum insulin levels were two-to threefold greater in hyperinsulinemic rats, whereas systolic blood pressures, food and water intake, serum triglyceride levels, plasma cortisol levels, and urinary catecholamine levels were not affected. Fourteen days after injury, neointima-to-media area ratios were 0.89 Ϯ 0.23 and 1.35 Ϯ 0.22 in control and hyperinsulinemic rats, respectively (P Ͻ 0.01). PTP1B protein levels and total PTP1B activity in injured carotid arteries from the insulin-treated group were significantly decreased 7 or 14 days after injury, whereas PTP1B specific activity was decreased only 14 days after injury. These findings were associated with decreased PTP1B mRNA levels and increased PDGFR tyrosyl phosphorylation in insulin-treated rats. These observations support the hypothesis that hyperinsulinemia induces the suppression of PTP1B function, leading to enhanced PDGFR signaling and neointimal hyperplasia. restenosis; reverse transcription-polymerase chain reaction; vascular injury; protein tyrosine phosphatase 1B; platelet-derived growth factor HYPERINSULINEMIA is a key feature of metabolic syndrome and type 2 diabetes (18). Moreover, plasma insulin levels in the population of the United States appear to have increased by ϳ35% during the last decade (32). It is now well accepted that metabolic syndrome and type 2 diabetes are strongly associated with adverse cardiovascular events in humans, although the underlying reasons for these associations have not been clarified (3,12,44,49,55). Several recent studies have reported that hyperinsulinemia is associated with vascular remodeling and enhanced neointima formation in models of experimental vascular injury as well as in humans (20,28,37,39,55). Moreover, hyperinsulinemia, but not hyperglycemia, has been reported to induce enhanced neointima formation in models of rat vascular injury (11, 28).The migration of medial vascular smooth muscle cells to the intima and the subsequent cell proliferation are thought to be necessary for the vascular remodeling that occurs after injury or in atherosclerosis. Acute treatment with insulin has been reported to atte...

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“…In humans with insulin resistance, the frequency of restenosis after coronary angioplasty is significantly higher than those with normal insulinemia [4]. Animals with hyperinsulinemia show increased neointima formation caused by vascular injury via potentiating smooth muscle cell migration and proliferation [5][6][7]. The application of insulin sensitizers, such as synthetic thiazolidinediones (STD), significantly reduces carotid artery intima/ media thickness in patients with type 2 diabetes [8][9][10] and in animals with induced carotid injury [11][12][13][14].…”

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confidence: 99%

A Central Role of PTP1B in Hyperinsulinemia-Enhanced IL-6 Signaling in Dedifferentiated Vascular Smooth Muscle Cells

Chang¹

2011

J Diabet Metabol

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Hyperinsulinemia, a major feature of type 2 diabetes and the metabolic syndrome, is believed to be highly associated with the occurrence of atherosclerosis and vascular restenosis [1][2][3]. In humans with insulin resistance, the frequency of restenosis after coronary angioplasty is significantly higher than those with normal insulinemia [4]. Animals with hyperinsulinemia show increased neointima formation caused by vascular injury via potentiating smooth muscle cell migration and proliferation [5][6][7]. The application of insulin sensitizers, such as synthetic thiazolidinediones (STD), significantly reduces carotid artery intima/ media thickness in patients with type 2 diabetes [8][9][10] and in animals with induced carotid injury [11][12][13][14]. However, the underlying mechanisms are not well understood. Recurrent stenosis after angioplasty is the result of increased smooth muscle cell proliferation in the media layer and migration to the intima in the wall of the vasculature. It is well established that vascular inflammation in response to angioplasty-induced injury is the initiator of increased neointima formation. Several experimental and clinical observations indicate that up regulation of pro-inflammatory cytokines in activated SMCs contributes to angioplasty-induced restenosis through promoting vascular smooth muscle cell migration and proliferation, a manifestation of an inflammatory wound healing process occurring in injured vessels [15][16][17]. Of the many cytokines involved in injury-induced inflammation, IL-6 is the major pro-inflammatory cytokine that contributes to vascular injuryinduced neointima thickening [18]. IL-6 is expressed and synthesized by a variety of cell types implicated in intimal hyperplasia. These include endothelial cells, macrophages, and smooth muscle cells. IL-6 induces a motogenic effect on vascular smooth muscle cells [19,20]. A significant correlation between the changes of IL-6 concentrations in the coronary circulation after PTCA and the degree of restenosis has been observed [21]. Monitoring variations in IL-6 has been proposed as an inflammatory marker to detect the early stage of cardiovascular diseases in order to develop a beneficial strategy to prevent the progression of the diseases. It was also reported that IL-6 induced the expression of acute phase proteins and several other cytokines and growth factors [22], suggesting that IL-6 may serve as a major initiator to trigger inflammation cascade responses that later lead to restenosis. One of the signal transduction pathways that mediates IL-6-mediated cellular responses is gp130/JAK/ STAT cascade [19]. The formation of IL-6 and the IL-6 receptor complex promotes the recruitment of gp130, followed by activation of Janus kinase (JAK). Activation of JAKs leads to tyrosine phosphorylation of gp130 and recruitment of STAT 3 . STAT 3 in turn becomes phosphorylated and dimerized, and translocate into the nucleus, where it binds to the target genes and regulates gene transcription and protein expression [19], leading t...

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Insulin stimulates arterial neointima formation in normal rats after balloon injury

Abstract: The effects of hyperinsulinaemia which promote neointimal hyperplasia after balloon injury of rat carotid artery predominate over the effects which inhibit it even in normal animals.

Cited by 18 publications

References 16 publications

Insulin Inhibits and Oral Sucrose Increases Neointimal Growth after Arterial Injury in Rats

Insulin Inhibits and Oral Sucrose Increases Neointimal Growth after Arterial Injury in Rats

Chronic insulin treatment suppresses PTP1B function, induces increased PDGF signaling, and amplifies neointima formation in the balloon-injured rat artery

A Central Role of PTP1B in Hyperinsulinemia-Enhanced IL-6 Signaling in Dedifferentiated Vascular Smooth Muscle Cells

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