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Impaired synthesis and action of antiaggregating cyclic nucleotides in platelets from obese subjects: possible role in platelet hyperactivation in obesity
Author(s) -
Anfossi G.,
Russo I.,
Massucco P.,
Mattiello L.,
Doronzo G.,
De Salve A.,
Trovati M.
Publication year - 2004
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1111/j.1365-2362.2004.01370.x
Subject(s) - platelet , hyperactivation , nucleotide , obesity , endocrinology , medicine , action (physics) , chemistry , biochemistry , gene , physics , quantum mechanics
Background Subjects with central obesity exhibit platelet hyperactivity, which is involved in the atherosclerotic process and therefore can account for the increased risk of cardiovascular morbidity and mortality. The aim of the study was to evaluate whether alterations of platelet function in obesity involve synthesis and/or action of the two antiaggregating cyclic nucleotides adenosine 3′,5′‐cyclic monophosphate (cAMP) and guanosine 3′,5′‐cyclic monophosphate (cGMP). Materials and methods In platelets from 16 obese and 15 control subjects we investigated the influence on platelet responses to the Adenosine‐5‐diphosphate sodium salt (ADP) exerted by (i) prostacyclin analogue Iloprost (0·31–5 nmol L −1 ) and the cAMP analogue 8‐bromo‐cAMP (10–500 µmol L −1 ); and by (ii) nitric oxide (NO) donor sodium nitroprusside (SNP) (5–100 µmol L −1 ) and the cGMP analogue 8‐bromo‐cGMP (10–500 µmol L −1 ). IC 50 (minimal concentration of each inhibitor necessary to reduce platelet response to ADP by half) was determined. Iloprost and SNP ability to increase cyclic nucleotides was also measured. Results Significantly greater IC 50 were observed in obese subjects than in healthy controls (1·59 ± 0·16 vs. 0·80 ± 0·08 nmol L −1 , P = 0·0001 for Iloprost, and 27·6 ± 6·5 vs. 7·0 ± 1·7 µmol L −1 , P = 0·006, for SNP); when data from control and obese subjects were pooled together, IC 50 of Iloprost and SNP correlated with the homeostasis model assessment (HOMA IR), which is a parameter used to measure the insulin resistance ( r = 0·588, P = 0·029 and r = 0·640, P = 0·006, respectively). Also the antiaggregating effect of 8‐Br‐cAMP and 8‐Br‐cGMP was smaller in the obese subjects. Finally, the ability of Iloprost to increase platelet cAMP and the ability of SNP to increase both cGMP and cAMP were reduced in obese subjects. Conclusions Platelet resistance to the antiaggregating effects of prostacyclin and NO in obesity is attributable to impairment of cyclic nucleotide synthesis and action. As cyclic nucleotides are the main effectors of platelet antiaggregation, the resistance to them can account for platelet hyperactivity in obesity.