Chronic insulin treatment amplifies PDGF-induced motility in differentiated aortic smooth muscle cells by suppressing the expression and function of PTP1B

Dept. of Physiology, Univ. of Tennessee, Memphis, TN 38163, USA.
AJP Heart and Circulatory Physiology (Impact Factor: 3.84). 08/2008; 295(1):H163-73. DOI: 10.1152/ajpheart.01105.2007
Source: PubMed


Hyperinsulinemia plays a major role in the pathogenesis of vascular disease. Restenosis occurs at an accelerated rate in hyperinsulinemia and is dependent on increased vascular smooth muscle cell movement from media to neointima. PDGF plays a critical role in mediating neointima formation in models of vascular injury. We have reported that PDGF increases the levels of protein tyrosine phosphatase PTP1B and that PTP1B suppresses PDGF-induced motility in cultured cells and that it attenuates neointima formation in injured carotid arteries. Others have reported that insulin enhances the mitogenic and motogenic effects of PDGF in cultured smooth muscle cells and that hyperinsulinemia promotes vascular remodeling. In the present study, we tested the hypothesis that insulin amplifies PDGF-induced cell motility by suppressing the expression and function of PTP1B. We found that chronic but not acute treatment of cells with insulin enhances PDGF-induced motility in differentiated cultured primary rat aortic smooth muscle cells and that it suppresses PDGF-induced upregulation of PTP1B protein. Moreover, insulin suppresses PDGF-induced upregulation of PTP1B mRNA levels, PTP1B enzyme activity, and binding of PTP1B to the PDGF receptor-beta, and it enhances PDGF-induced PDGF receptor phosphotyrosylation. Treatment with insulin induces time-dependent upregulation of phosphatidylinositol 3-kinase (PI3-kinase)-delta and activation of Akt, an enzyme downstream of PI3-kinase. Finally, inhibition of PI3-kinase activity, or its function, by pharmacological or genetic means rescues PTP1B activity in insulin-treated cells. These observations uncover novel mechanisms that explain how insulin amplifies the motogenic capacity of the pivotal growth factor PDGF.

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    • "The level of insulin in macrosomic newborns, were significant correlated with the plasma PDGF-B levels (r = 0.53, n = 30, P = 0.017). Indeed, insulin has been shown to enhance the mitogenic effects of PDGFR-β in cultured smooth muscle cells where it interferes with the cell signaling cascade, particularly with phosphatidylinositol-3-kinase of PDGFR-β [46,47]. High PDGF-B levels via PDGFR-β may also participate in placental angiogenesis in GDM women [48]. "
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    ABSTRACT: Gestational diabetes mellitus (GDM) is a form of diabetes that occurs during pregnancy. GDM is a well known risk factor for foetal overgrowth, termed macrosomia which is influenced by maternal hypergycemia and endocrine status through placental circulation. The study was undertaken to investigate the implication of growth factors and their receptors in GDM and macrosomia, and to discuss the role of the materno-foeto-placental axis in the in-utero regulation of foetal growth. 30 women with GDM and their 30 macrosomic babies (4.75 +/- 0.15 kg), and 30 healthy age-matched pregnant women and their 30 newborns (3.50 +/- 0.10 kg) were recruited in the present study. Serum concentrations of GH and growth factors, i.e., IGF-I, IGF-BP3, FGF-2, EGF and PDGF-B were determined by ELISA. The expression of mRNA encoding for GH, IGF-I, IGF-BP3, FGF-2, PDGF-B and EGF, and their receptors, i.e., GHR, IGF-IR, FGF-2R, EGFR and PDGFR-beta were quantified by using RT-qPCR. The serum concentrations of IGF-I, IGF-BP3, EGF, FGF-2 and PDGF-B were higher in GDM women and their macrosomic babies as compared to their respective controls. The placental mRNA expression of the growth factors was either upregulated (FGF-2 or PDGF-B) or remained unaltered (IGF-I and EGF) in the placenta of GDM women. The mRNA expression of three growth factor receptors, i.e., IGF-IR, EGFR and PDGFR-beta, was upregulated in the placenta of GDM women. Interestingly, serum concentrations of GH were downregulated in the GDM women and their macrosomic offspring. Besides, the expression of mRNAs encoding for GHR was higher, but that encoding for GH was lower, in the placenta of GDM women than control women. Our results demonstrate that growth factors might be implicated in GDM and, in part, in the pathology of macrosomia via materno-foeto-placental axis.
    BMC Pregnancy and Childbirth 02/2010; 10(1):7. DOI:10.1186/1471-2393-10-7 · 2.19 Impact Factor
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    • "In cells cultured for 7 days in 22.5 mM D-glucose, both oxidant and insulin stimulation (for 10 min) up-regulated Akt phosphorylation by $3-and 2-fold, respectively (versus the level in non-stimulated cells grown in high glucose condition). Although the activating effect of H 2 O 2 and insulin on vascular SMCs Akt is known [11] [13] [26], we demonstrate here that it is produced also in SMCs affected by the longterm maintenance in high glucose. ERK1/2 phosphorylation is up-regulated by prolonged culture in high glucose and acute oxidative stress stimulation "
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    ABSTRACT: Hyperglycemia stimulates a plethora of intracellular signaling pathways within the cells of the vascular wall resulting in dysfunction-associated pathologies. Most of the studies reported so far explored the effect of rather short-time exposure of smooth muscle cells to high glucose concentrations. To mimic situation in Type 2 diabetes in which vascular wall is constantly exposed to circulating hyperglycemia, we report here the long-term (7days) effect of high glucose concentration on human media artery smooth muscle cells. This consists in up-regulation of PTP1B protein expression, down-regulation of basal Akt phosphorylation, and elevation of basal ERK1/2 activation. Acute stimulation of cells in high glucose with insulin down-regulated PTP1B expression, slightly decreased ERK1/2 activity, and activated Akt, whereas oxidative stress up-regulated Akt and ERK1/2 phosphorylation. In conclusion, long-term high glucose and acute oxidative stress and insulin stimulation imbalance the expression of activated kinases Akt and ERK1/2 and of dephosphorylating PTP1B in the insulin signaling pathway.
    Biochemical and Biophysical Research Communications 09/2009; 388(1):51-5. DOI:10.1016/j.bbrc.2009.07.141 · 2.30 Impact Factor
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    ABSTRACT: 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 +/- 0.23 and 1.35 +/- 0.22 in control and hyperinsulinemic rats, respectively (P < 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.
    AJP Heart and Circulatory Physiology 11/2008; 296(1):H132-9. DOI:10.1152/ajpheart.00370.2008 · 3.84 Impact Factor
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