Glucose lowers the threshold for human aortic vascular smooth muscle cell migration: inhibition by protein phosphatase-2A

AIMS/HYPOTHESIS: Atherosclerosis, which occurs prematurely in individuals with diabetes, incorporates vascular smooth muscle cell (VSMC) chemotaxis. Glucose, through protein kinase C-beta(II) signalling, increases chemotaxis to low concentrations of platelet-derived growth factor (PDGF)-BB. In VSMC, a biphasic response in PDGF-beta receptor (PDGF-betaR) level occurs as PDGF-BB concentrations increase. The purpose of this study was to determine whether increased concentrations of PDGF-BB and raised glucose level had a modulatory effect on the mitogen-activated protein kinase/extracellular-regulated protein kinase pathway, control of PDGF-betaR level and chemotaxis.

METHODS: Cultured aortic VSMC, exposed to normal glucose (NG) (5 mmol/l) or high glucose (HG) (25 mmol/l) in the presence of PDGF-BB, were assessed for migration (chemotaxis chamber) or else extracted and immunoblotted.

RESULTS: At concentrations of PDGF-BB <540 pmol/l, HG caused an increase in the level of PDGF-betaR in VSMC (immunoblotting) versus NG, an effect that was abrogated by inhibition of aldose reductase or protein kinase C-beta(II). At higher concentrations of PDGF-BB (>540 pmol/l) in HG, receptor level was reduced but in the presence of aldose reductase or protein kinase C-beta(II) inhibitors the receptor levels increased. It is known that phosphatases may be activated at high concentrations of growth factors. At high concentrations of PDGF-BB, the protein phosphatase (PP)2A inhibitor, endothall, caused an increase in PDGF-betaR levels and a loss of biphasicity in receptor levels in HG. At higher concentrations of PDGF-BB in HG, the chemoattractant effect of PDGF-BB was lost (chemotaxis chamber). Under these conditions inhibition of PP2A was associated with a restoration of chemotaxis to high concentrations of PDGF-BB.

CONCLUSION/INTERPRETATION: The biphasic response in PDGF-betaR level and in chemotaxis to PDGF-BB in HG is due to PP2A activation.

Ocular blood flow analysis detects microvascular abnormalities in impaired glucose tolerance.

Objective: Waveform analysis has been used to assess vascular resistance and predict cardiovascular events. We aimed to identify microvascular abnormalities in patients with impaired glucose tolerance (IGT) using ocular waveform analysis. The effects of pioglitazone were also assessed. Methods: Forty patients with IGT and twenty-four controls were studied. Doppler velocity recordings were obtained from the central retinal, ophthalmic and common carotid arteries, and sampled at 200 Hz. A discrete wavelet-based analysis method was employed to quantify waveforms. The resistive index (RI),was also determined. Patients with IGT were randomised to pioglitazone or placebo and measurements repeated after 12 weeks treatment. Results: In the ocular waveforms, significant differences in power spectra were observed in frequency band four (corresponding to frequencies between 6.25 and 12.50 Hz) between groups (p

Neutron diffraction, NMR and molecular dynamics study of glucose dissolved in the ionic liquid 1-ethyl-3-methylimidazolium acetate

beta-D-glucose dissolved in the ionic liquid 1-ethyl-3-methylimidazolium acetate in a 6 : 1 molar ratio (ionic liquid : glucose) has been studied by neutron scattering, NMR and molecular dynamics simulations. Good agreement was found between simulated neutron scattering profiles generated for isotopically substituted liquid systems and those experimentally determined as well as between simulated and experimental diffusion coefficients obtained by Pulsed Field Gradient NMR spectroscopy. The overriding glucose-ionic liquid interactions in the liquid are hydrogen-bonding between acetate oxygens and sugar hydroxyl groups. The ionic liquid cation was found to play only a minor role in the solvation of the sugar and does not participate in hydrogen-bonding with the sugar to any significant degree. NOESY experiments lend further evidence that there is no direct interaction between sugar hydroxyl groups and acidic hydrogens on the ionic liquid cation.