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This Article Full Text Full Text (PDF) All Versions of this Article: clinchem.2006.076208v1 53/6/1053    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Russo, I. Articles by Anfossi, G. Search for Related Content PubMed PubMed Citation Articles by Russo, I. Articles by Anfossi, G. Related Collections Hemostasis and Thrombosis

Platelet Resistance to the Antiaggregatory Cyclic Nucleotides in Central Obesity Involves Reduced Phosphorylation of Vasodilator-Stimulated Phosphoprotein

Diabetes Unit, Department of Clinical and Biological Sciences of the University of Turin, San Luigi Gonzaga Hospital, Orbassano (Turin), Italy.

^aAddress correspondence to this author at: Diabetes Unit, Department of Clinical and Biological Sciences of the University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano (Turin), Italy. Fax 39-011-9038639; e-mail giovanni.anfossi{at}unito.it.

Background: Impairment of platelet response to antiaggregatory agents is seen in individuals with central obesity and may play a role in the increased cardiovascular risk associated with obesity. In this study we evaluated whether this impairment involves the antiaggregatory pathways regulated by cAMP and cGMP.

Methods: We obtained platelet-rich plasma from 12 obese individuals and 12 controls. We investigated the effects of the cyclic nucleotide analogs 8-pCPT-cAMP (10–500 µmol/L) and 8-pCPT-cGMP (10–500 µmol/L) on ADP-induced platelet aggregation as assessed by decreased light scattering. We assessed the activation of cAMP- and cGMP-dependent protein kinases by measuring phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) at Ser157 and Ser239.

Results: The antiaggregatory effect of both cyclic nucleotide analogs was impaired in obese individuals compared to controls, with mean (SE) half-maximal inhibitory concentrations (IC₅₀) (after 20-min incubation) of 123 (33) µmol/L vs 5 (1) µmol/L, respectively, for 8-pCPT-cAMP (P <0.01) and of 172 (43) µmol/L vs 17 (8) µmol/L, respectively, for 8-pCPT-cGMP (P <0.01). The Homeostasis Model Assessment Index of Insulin Resistance was independently correlated with cyclic nucleotide analog IC₅₀. In obese individuals, VASP phosphorylation at Ser157 and Ser239 in response to cyclic nucleotides was significantly lower than in controls.

Conclusions: In central obesity the reduced ability of cyclic nucleotides to inhibit platelet aggregation is associated with reduced activation of their specific kinases. Because cyclic nucleotides help regulate platelet antiaggregation, alteration of this ability is consistent with platelet hyperactivity in obesity.

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				I. Russo, P. Del Mese, G. Doronzo, L. Mattiello, M. Viretto, A. Bosia, G. Anfossi, and M. Trovati Resistance to the Nitric Oxide/Cyclic Guanosine 5'-Monophosphate/Protein Kinase G Pathway in Vascular Smooth Muscle Cells from the Obese Zucker Rat, a Classical Animal Model of Insulin Resistance: Role of Oxidative Stress Endocrinology, April 1, 2008; 149(4): 1480 - 1489. [Abstract] [Full Text] [PDF]