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Extracellular-Nitric Oxide-Mediated Platelet-cGMP Production in Type 2 Diabetics Correlates Inversely with Plasma Membrane Cholesterol Levels
No full textRecently, 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
Atorvastatin increases ecNOS levels in human platelets of hyperlipidemic subjects
No full textBACKGROUND: The purpose of this study was to probe the pleiotrophic effects of Atorvastatin on intraplatelet-nitric oxide metabolism.
METHODS AND RESULTS: Hyperlipidemic subjects (n = 19) were treated for 1 month (following a 3-week washout) with either Atorvastatin or placebo in a double-blinded randomized (n = 2, crossover), placebo-controlled study. Changes in the levels of intraplatelet nitric oxide synthase, nitrotyrosine were correlated with cholesterol, LDL-C, HDL-C and triglyceride levels. These studies indicate that with atrovastatin ecNOS levels increased on average by approximately approximately 1.7-fold (paired t-test p = 0.009). Interestingly, levels of nitrotyrosylated platelet proteins, an indication of peroxynitrite damage, decreased as ecNOS levels increased in presence of the drug (paired t-test p = 0.33). Atorvastatin, at 10 mg per day, lowered cholesterol and LDL-C levels in all patients with the average lowering of approximately 21% and approximately 17% respectively. The effect on HDL was not significant whilst triglyceride levels were lowered by an average of approximately 18%.
CONCLUSIONS: This study adds to the volume of evidence that statins have beneficial effects other than lipid lowering. Here, Atorvastatin is shown to significantly elevate intraplatelet ecNOS levels in hyperlipidemic subjects without affecting iNOS expression. The net result of this would be the elevation of NO production which would promote platelet deaggregation and vasodilation
N-dansylhomocysteine-NO, a new fluorogenic reagent for potential use as a probe for cellular NO utilization.
No full textAn in vitro study of the interactions between lipoproteins and membrane platelets in the obesity.
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Homocysteine-induced inhibition of nitric oxide production in platelets: a study on healthy and diabetic subjects.
No full textDirect correlation between serum LDL-Chol and platelet plasma membrane cholesterol levels.
No full textEvidence for S-nitrosothiol-dependent changes in fibrinogen that do not involve transnitrosation or thiolation
No full textS-nitrosoglutathione (GSNO, 50 microM) inhibited the initial rate of thrombin-catalyzed human and bovine fibrinogen polymerization by approximately 50% to 68% respectively. Inhibition was also observed with other structurally varied S-nitrosothiols (RSNOs) including sugar derivatives of S-nitroso-N-acetylpenicillamine (SNAP). The fact that the same concentration of GSNO had no effect on thrombin-dependent hydrolysis of tosylglycylprolylarginine-4-nitroanilide acetate suggested that this inhibition was due to GSNO-induced changes in fibrinogen structure. This result was confirmed by CD spectroscopy where GSNO or S-nitrosohomocysteine increased the alpha-helical content of fibrinogen by approximately 15% and 11%, respectively. S-carboxymethylamido derivatives of glutathione or homocysteine had no effect on the fibrinogen secondary structure. The GSNO-dependent secondary structural effects were reversed on gel filtration chromatography, suggesting that the effects were allosteric. Further evidence for fibrinogen-GSNO interactions was obtained from GSNO-dependent quenching of the intrinsic fibrinogen Trp fluorescence and the perturbation of the GSNO circular dichroic absorbance as a function of [fibrinogen]. The K(d)s of 3 to 10 microM for fibrinogen-GSNO interactions with a stoichiometry of 2:1 (GSNO:fibrinogen) were estimated from isothermal titration calorimetry and fluorescence quenching, respectively. These results suggest that RSNOs induce changes to fibrinogen structure by interacting at specific aromatic rich domains. Three such putative RSNO-binding domains have been identified in the unordered, aromatic residue-rich C-termini of the alpha-chains of fibrinogen
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