Insulin enhances the effect of nitric oxide at inhibiting neointimal hyperplasia in a rat model of type 1 diabetes
Division of Vascular Surgery and Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, IL 60611, USA. AJP Heart and Circulatory Physiology
(Impact Factor: 3.84).
09/2010; 299(3):H772-9. DOI: 10.1152/ajpheart.01234.2009
Diabetes confers greater restenosis from neointimal hyperplasia following vascular interventions. While localized administration of nitric oxide (NO) is known to inhibit neointimal hyperplasia, the effect of NO in type 1 diabetes is unknown. Thus the aim of this study was to determine the efficacy of NO following arterial injury, with and without exogenous insulin administration. Vascular smooth muscle cells (VSMC) from lean Zucker (LZ) rats were exposed to the NO donor, DETA/NO, following treatment with different glucose and/or insulin concentrations. DETA/NO inhibited VSMC proliferation in a concentration-dependent manner to a greater extent in VSMC exposed to normal-glucose vs. high-glucose environments, and even more effectively in normal-glucose/high-insulin and high-glucose/high-insulin environments. G(0)/G(1) cell cycle arrest and cell death were not responsible for the enhanced efficacy of NO in these environments. Next, type 1 diabetes was induced in LZ rats with streptozotocin. The rat carotid artery injury model was performed. Type 1 diabetic rats experienced no significant reduction in neointimal hyperplasia following arterial injury and treatment with the NO donor PROLI/NO. However, daily administration of insulin to type 1 diabetic rats restored the efficacy of NO at inhibiting neointimal hyperplasia (60% reduction, P < 0.05). In conclusion, these data demonstrate that NO is ineffective at inhibiting neointimal hyperplasia in an uncontrolled rat model of type 1 diabetes; however, insulin administration restores the efficacy of NO at inhibiting neointimal hyperplasia. Thus insulin may play a role in regulating the downstream beneficial effects of NO in the vasculature.
Available from: Xingjian Chen
- "Lean Zucker rats fattened by a high-fat diet for one month developed hyperinsulinemia but had normal blood pressure, similar to other reports
[31,32]. To establish a hyperglycemia model, lean Zucker rats were intraperitoneally injected with a single dose of STZ (65 mg/kg)
; the STZ-treated lean Zucker rats would be expected to develop slightly high blood pressure and hyperglycemia but with low plasma insulin levels (Table
1), as described by others
. We found that both hyperinsulinemic (Figure
4A) and hyperglycemic (Figure
4B) lean Zucker rats had impaired D1 receptor-mediated vasorelaxation, accompanied by decreased D1 receptor expression (Figure
4C) and increased D1 receptor phosphorylation (Figure
4D), but the dysfunction of the D1 receptor was greater in the hyperinsulinemia than hyperglycemia model, indicating that insulin plays a more important role than hyperglycemia in the impairment of arterial D1 receptor-mediated relaxation (Figures
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ABSTRACT: Obesity plays an important role in the pathogenesis of hypertension. Renal dopamine D1-like receptor-mediated diuresis and natriuresis are impaired in the obese Zucker rat, an obesity-related hypertensive rat model. The role of arterial D1 receptors in the hypertension of obese Zucker rats is not clear.
Plasma glucose and insulin concentrations and blood pressure were measured. The vasodilatory response of isolated mesenteric arteries was evaluated using a small vessel myograph. The expression and phosphorylation of D1 receptors were quantified by co-immunoprecipitation and immunoblotting To determine the effect of hyperinsulinemia and hyperglycemia on the function of the arterial D1 receptor, we studied obese Zucker rats (six to eight-weeks old) fed (6 weeks) vehicle or rosiglitazone, an insulin sensitizer (10 mg/kg per day) and lean Zucker rats (eight to ten-weeks old), fed high-fat diet to induce hyperinsulinemia or injected intraperitoneally with streptomycin (STZ) to induce hyperglycemia.
In obese Zucker rats, the vasorelaxant effect of D1-like receptors was impaired that could be ascribed to decreased arterial D1 receptor expression and increased D1 receptor phosphorylation. In these obese rats, rosiglitazone normalized the arterial D1 receptor expression and phosphorylation and improved the D1-like receptor-mediated vasorelaxation. We also found that D1 receptor-dependent vasorelaxation was decreased in lean Zucker rats with hyperinsulinemia or hyperglycemia but the D1 receptor dysfunction was greater in the former than in the latter group. The ability of insulin and glucose to decrease D1 receptor expression and increase its phosphorylation were confirmed in studies of rat aortic smooth muscle cells.
Both hyperinsulinemia and hyperglycemia caused D1 receptor dysfunction by decreasing arterial D1 receptor expression and increasing D1 receptor phosphorylation. Impaired D1 receptor-mediated vasorelaxation is involved in the pathogenesis of obesity-related hypertension.
Cardiovascular Diabetology 02/2014; 13(1):50. DOI:10.1186/1475-2840-13-50 · 4.02 Impact Factor
Available from: accelconf.web.cern.ch
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ABSTRACT: A linac beam profile measurement system using wire scanners has been implemented at the Bates Linear Accelerator Center. Obtaining an optimum linac focussing solution is facilitated by the system. A nearly noninvasive beam size measurement is made of the two beams which are accelerated simultaneously in the recirculating linac. The wire scanner's mechanical accuracy is near one mil. Beam size measurements are reproducible to a few mils
Biomedical Engineering Conference, 1998. Proceedings of the 17th Southern; 03/1998
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