Impaired synthesis and action of antiaggregating cyclic nucleotides in platelets from obese subjects: Possible role in platelet hyperactivation in obesity

G. Anfossi, I. Russo, P. Massucco, L. Mattiello, G. Doronzo, A. De Salve, M. Trovati

Research output: Contribution to journalArticle

Abstract

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). IC50 (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 IC50 were observed in obese subjects than in healthy controls (1.59 ± 0.16 vs. 0.80 ± 0.08 nmol L-1, P = 0.001 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, IC50 of Iloprost and SNP correlated with the homeostasis model assessment (HOMAIR), 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.

Original languageEnglish
Pages (from-to)482-489
Number of pages8
JournalEuropean Journal of Clinical Investigation
Volume34
Issue number7
DOIs
Publication statusPublished - Jul 2004

Fingerprint

Cyclic Nucleotides
Platelets
Blood Platelets
Obesity
Iloprost
Nitroprusside
Guanosine
Adenosine Diphosphate
Inhibitory Concentration 50
8-Bromo Cyclic Adenosine Monophosphate
Epoprostenol
Nitric Oxide Donors
Abdominal Obesity
Cyclic GMP
Adenosine
Insulin Resistance
Healthy Volunteers
Nitric Oxide
Homeostasis
Salts

Keywords

  • Cyclic AMP
  • Cyclic GMP
  • Insulin resistance
  • Nitric oxide
  • Obesity
  • Platelets
  • Prostacyclin

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Impaired synthesis and action of antiaggregating cyclic nucleotides in platelets from obese subjects : Possible role in platelet hyperactivation in obesity. / Anfossi, G.; Russo, I.; Massucco, P.; Mattiello, L.; Doronzo, G.; De Salve, A.; Trovati, M.

In: European Journal of Clinical Investigation, Vol. 34, No. 7, 07.2004, p. 482-489.

Research output: Contribution to journalArticle

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T2 - Possible role in platelet hyperactivation in obesity

AU - Anfossi, G.

AU - Russo, I.

AU - Massucco, P.

AU - Mattiello, L.

AU - Doronzo, G.

AU - De Salve, A.

AU - Trovati, M.

PY - 2004/7

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N2 - 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). IC50 (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 IC50 were observed in obese subjects than in healthy controls (1.59 ± 0.16 vs. 0.80 ± 0.08 nmol L-1, P = 0.001 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, IC50 of Iloprost and SNP correlated with the homeostasis model assessment (HOMAIR), 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.

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KW - Cyclic GMP

KW - Insulin resistance

KW - Nitric oxide

KW - Obesity

KW - Platelets

KW - Prostacyclin

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