Diabetes-related changes in cAMP response element-binding protein content enhance smooth muscle cell proliferation and migration

We hypothesized that diabetes and glucose-induced reactive oxygen species l ead to depletion of cAMP response element-binding protein (CREB) content in the vasculature. In primary cultures of smooth muscle cells (SMC) high med ium glucose decreased CREB function but increased SMC chemokinesis and entr y into the cell cycle. These effects were blocked by pretreatment with the antioxidants. High glucose increased intracellular reactive oxygen species detected by CM-H(2)DCFA. SMC exposed to oxidative stress (H2O2) demonstrate d a 3.5-fold increase in chemokinesis (p < 0.05) and accelerated entry into cell cycle, accompanied by a significant decrease in CREB content. Chronic oxidative challenge similar to the microenvironment in diabetes (glucose o xidase treatment) decreases CREB content (40-50%). Adenoviral-mediated expr ession of constitutively active CREB abolished the increase in chemokinesis and cell cycle progression induced by either high glucose or oxidative str ess. Analysis of vessels from insulin resistant or diabetic animals indicat es that CREB content is decreased in the vascular stroma. Treatment of insu lin-resistant animals with the insulin sensitizer rosiglitazone restores ve ssel wall CREB content toward that observed in normal animals. In summary, high glucose and oxidative stress decrease SMC CREB content increase chemok inesis and entry into the cell cycle, which is blocked by antioxidants or r estoration of CREB content. Thus, decreased vascular CREB content could be one of the molecular mechanisms leading to increased atherosclerosis in dia betes.