Although hyperglycemia is an independent risk factor for vascular diseases, the links between glucose metabolism and atherosclerosis still require elucidation. We have previously shown that vascular cells, which regulates the glucose entry, are not damaged by high glucose concentrations unless they are primed with an inflammatory stimulus like interleukin (IL)1β. We now analyze the mechanisms accounting for the synergism between high glucose and IL1β. Under high glucose conditions (22 mmol/L), cultured human aortic smooth muscle cells (HASMC) exhibited excess glucose uptake and consumption (from 4.2±0.6 to 7.5±0.7 pmol per cell/24 h) associated to increased GLUT1 transporters expression only when co-stimulated with 10 ng/mL IL1β. However, the simple excess entry of glucose was not deleterious in these cells, as the inhibition of mitochondrial respiration with 0.5 mmol/L sodium azide increased glucose uptake and consumption (from 6.0±0.1 to 13.2±0.8 pmol per cell/24 h) without triggering inflammatory responses, measured by NF-κB activation and iNOS expression. We found that, besides allowing glucose entry, IL1β enhances glucose-6-phosphate dehydrogenase (G6PD) expression by 3.6±1.0 fold and activates the pentose phosphate pathway (PPP) from 9.6±0.7 to 17.4±1.5 nmol/h.mg prot in HASMC submitted to high glucose, thus permitting some of the excess glucose to be metabolized by this route. This provides additional substrate for enhancing the NADPH oxidase enzymatic activity by from 472±30 to 785±41 RLUS/μg prot/min, producing superoxide anions that are required for the activation of NF-κB and iNOS. The higher the concentration of glucose the more the PPP pathway is activated, giving rise to an increased inflammatory condition which cannot be counterbalanced by the simultaneous regeneration of reduced glutathione. We conclude that IL1β transforms excess glucose into a deleterious agent in HASMC by increasing glucose uptake, which is diverted into the PPP, promoting the pro-oxidant conditions required for the exaggeration of inflammatory pathways. Interestingly, all these pathways were blocked with the IL1 receptor antagonist anakinra (1 μmol/L), suggesting this anti-inflammatory drug can be effective for preventing diabetic vasculopathy.
High Glucose-Induced Upregulation of Osteopontin Is Mediated via Rho/Rho Kinase Pathway in Cultured Rat Aortic Smooth Muscle Cells
