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1.
J Vasc Res ; 50(4): 279-88, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23988659

RESUMO

UNLABELLED: In vitro, insulin has both growth-promoting and vasculoprotective effects. In vivo, the effect of insulin is mainly protective. Insulin treatment (3 U/day) decreases smooth muscle cell (SMC) migration and neointimal growth after carotid angioplasty in normal rats maintained at normoglycemia by oral glucose. SMC migration requires limited proteolysis of the extracellular matrix, which is mediated by matrix metalloproteinases (MMPs). In this study, we investigated the effects of normoglycemic hyperinsulinemia on MMP activity after balloon angioplasty. Rats were divided into three groups: (1) control implants and tap water; (2) control implants and oral glucose, and (3) insulin implants (3 U/day) and oral glucose. RESULTS: Gelatin zymography revealed that insulin reduced the gelatinolytic activity of pro-MMP-2 by 46% (p < 0.05), MMP-2 by 44% (p < 0.05) and MMP-9 by 51% (p < 0.05) compared to controls after arterial injury. Insulin also reduced mRNA levels of MMP-2 (p < 0.05) and MMP-9 (p < 0.05) and protein levels of MMP-2 (p < 0.05). In contrast, there were no significant changes in membrane-type 1 MMP protein and tissue inhibitors of MMP activity after insulin treatment. Thus, these results suggest a mechanism by which insulin inhibits SMC migration and supports a vasculoprotective role for insulin in vivo.


Assuntos
Lesões das Artérias Carótidas/tratamento farmacológico , Artéria Carótida Primitiva/efeitos dos fármacos , Insulina/farmacologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Lesões do Sistema Vascular/tratamento farmacológico , Administração Oral , Angioplastia com Balão , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Lesões das Artérias Carótidas/enzimologia , Lesões das Artérias Carótidas/etiologia , Artéria Carótida Primitiva/enzimologia , Modelos Animais de Doenças , Regulação para Baixo , Implantes de Medicamento , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glucose/administração & dosagem , Insulina/administração & dosagem , Insulina/sangue , Masculino , Metaloproteinase 14 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Inibidores Teciduais de Metaloproteinases/metabolismo , Lesões do Sistema Vascular/enzimologia , Lesões do Sistema Vascular/etiologia
2.
J Vasc Res ; 47(5): 412-22, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20145414

RESUMO

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.


Assuntos
Lesões das Artérias Carótidas/patologia , Insulina/farmacologia , Sacarose/farmacologia , Túnica Íntima/patologia , Administração Oral , Angioplastia com Balão/efeitos adversos , Animais , Dislipidemias/metabolismo , Dislipidemias/patologia , Jejum , Glucose/farmacologia , Insulina/sangue , Masculino , Ratos , Sacarose/administração & dosagem , Túnica Média/patologia
3.
Arterioscler Thromb Vasc Biol ; 29(7): 1060-6, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19359661

RESUMO

OBJECTIVE: Insulin has both growth-promoting and protective vascular effects in vitro, however the predominant effect in vivo is unclear. We investigated the effects of insulin in vivo on neointimal growth after arterial injury. METHODS AND RESULTS: Rats were given subcutaneous control (C) or insulin implants (3U/d;I) 3 days before arterial (carotid or aortic) balloon catheter injury. Normoglycemia was maintained by oral glucose and, after surgery, by intraperitoneal glucose infusion (saline in C). Insulin decreased intimal area (P<0.01) but did not change intimal cell proliferation or apoptosis. However, insulin inhibited cell migration into the intima (P<0.01) and increased expression of smooth muscle cell (SMC) differentiation markers (P<0.05). Insulin also increased reendothelialization (P<0.01) and the number of circulating progenitor cells (P<0.05). CONCLUSIONS: These results are the first demonstration that insulin has a protective effect on both SMC and endothelium in vivo, resulting in inhibition of neointimal growth after vessel injury.


Assuntos
Doenças das Artérias Carótidas/fisiopatologia , Movimento Celular/fisiologia , Insulina/fisiologia , Músculo Liso Vascular/fisiopatologia , Túnica Íntima/fisiopatologia , Angioplastia Coronária com Balão/efeitos adversos , Animais , Reestenose Coronária/fisiopatologia , Endotélio Vascular , Resistência à Insulina/fisiologia , Masculino , Músculo Liso Vascular/lesões , Miócitos de Músculo Liso/fisiologia , Ratos
4.
J Vasc Res ; 42(6): 455-62, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16155361

RESUMO

Metabolic syndrome is a risk factor for atherosclerosis and restenosis. In metabolic syndrome, insulin resistance coexists with hyperinsulinemia and hyperlipidemia. Hyperlipidemia has growth-promoting effects, whereas insulin has both growth-promoting and growth-inhibitory effects on vascular smooth muscle cells in vitro. The objective of this study was to investigate the effects of hyperlipidemia and hyperinsulinemia on vascular cell growth in vivo after arterial injury. Rats fed a low-fat diet were treated with either subcutaneous blank (LFC) or insulin (LFI) implants. Rats fed a high-fat diet also received blank (HFC) or insulin (HFI) implants. After 3 days, rats received balloon carotid injury, and 14 days later they were sacrificed to measure neointimal area and proliferation. Hyperinsulinemia was present in LFI and HFI and hyperlipidemia was present in HFC and HFI. Neointimal area was higher in HFC (0.153 +/- 0.009 mm(2), p < 0.05) but lower in LFI (0.098 +/- 0.005, p < 0.01) than LFC (0.127 +/- 0.005). In HFI (0.142 +/- 0.008, p < 0.05) neointimal area was not different from HFC or LFC. In conclusion, insulin reduced neointimal growth, but the effect of insulin was diminished by the high-fat diet. Thus, our results demonstrate an anti-atherogenic effect of insulin in vivo and suggest that in metabolic syndrome insulin resistance rather than hyperinsulinemia is the atherogenic risk factor.


Assuntos
Aterosclerose/prevenção & controle , Insulina/farmacologia , Animais , Artérias Carótidas/patologia , Lesões das Artérias Carótidas/complicações , Lesões das Artérias Carótidas/etiologia , Lesões das Artérias Carótidas/patologia , Lesões das Artérias Carótidas/fisiopatologia , Cateterismo , Divisão Celular/efeitos dos fármacos , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/farmacologia , Relação Dose-Resposta a Droga , Implantes de Medicamento , Hiperinsulinismo/complicações , Hiperlipidemias/complicações , Insulina/administração & dosagem , Masculino , Ratos , Ratos Sprague-Dawley , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/patologia
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