Extracellular-Nitric Oxide-Mediated Platelet-cGMP Production in Type 2 Diabetics Correlates Inversely with Plasma Membrane Cholesterol Levels

Recently, we showed that the diffusion of nitric oxide (NO) and NO-mediated signaling was affected by the levels of plasma membrane cholesterol in fibroblasts. The generality of these observations, which would imply that perturbations in NO-signaling mediated by increased membrane cholesterol levels, could be a common pathological trigger in vascular cells, was tested in platelets from normal and dyslipidemic type 2 diabetic (T2D) subjects. Plasma LDL-cholesterol correlated directly with platelet plasma membrane cholesterol (Y=0.28X+0.16; R2=0.39). The average platelet plasma membrane cholesterol concentration was ~2-fold larger in T2D than in control subjects (P<0.05). Cyclic GMP production in response to exogenous NO was ~4-fold larger in controls than in T2D (P<0.05). Artificial elevation of membrane cholesterol resulted in ~50 % decrease in the initial rates of NO-uptake. Elevated plasma cholesterol could be a contributing factor to T2D-induced platelet hyperactivity, since it correlated with increased plasma membrane cholesterol, the attenuation of NO-diffusion into platelets and the lowering of cGMP biosynthesis.