Platelet resistance to the antiaggregatory cyclic nucleotides in central obesity involves reduced phosphorylation of vasodilator-stimulated phosphoprotein.
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 micromol/L) and 8-pCPT-cGMP (10-500 micromol/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 (IC(50)) (after 20-min incubation) of 123 (33) micromol/L vs 5 (1) micromol/L, respectively, for 8-pCPT-cAMP (P <0.01) and of 172 (43) micromol/L vs 17 (8) micromol/L, respectively, for 8-pCPT-cGMP (P <0.01). The Homeostasis Model Assessment Index of Insulin Resistance was independently correlated with cyclic nucleotide analog IC(50). 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.
Russo
Isabella
I
Diabetes Unit, Department of Clinical and Biological Sciences of University of Turin, San Luigi Gonzaga Hospital, Orbassano (Turin), Italy.
Del Mese
Paola
P
Doronzo
Gabriella
G
De Salve
Alessandro
A
Secchi
Mariantonietta
M
Trovati
Mariella
M
Anfossi
Giovanni
G
D000328:Adult; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004351:Drug Resistance; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008027:Light; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism*; D009712:Nucleotides, Cyclic / Q000494:pharmacology*; D009765:Obesity / Q000097:blood*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D012542:Scattering, Radiation; D013873:Thionucleotides / Q000494:pharmacology; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D009712:Nucleotides, Cyclic; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D013873:Thionucleotides; D000098662:Vasodilator-Stimulated Phosphoprotein; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; C055656:8-((4-chlorophenyl)thio)cyclic-3',5'-GMP; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP