Received on July 22, 2006
Accepted on March 16, 2007

Hemostasis and Thrombosis

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

¹ Diabetes Unit, Department of Clinical and Biological Sciences of the University of Turin, San Luigi Gonzaga Hospital, Orbassano (Turin), Italy

^* To whom correspondence should be addressed. 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.

Patients and 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.