title: Dehydroepiandrosterone-sulfate inhibits thrombin-induced platelet aggregation.
abstract: Dehydroepiandrosterone (DHEA) and its sulfated form, DHEA-S, are the most abundant steroids circulating in human blood. DHEA stimulates endothelial cells to release high amounts of nitric oxide in the circulation. Nitric oxide activates guanylyl cyclase in platelets thus decreasing the responsiveness of these cells to physiological agonists. However, the impact of DHEA-S and DHEA on platelet function and their possible role in modulating the response of human platelets to physiological agonists were not yet investigated. Here, DHEA-S, but not DHEA, inhibited in vitro thrombin-dependent platelet aggregation in a dose-dependent manner. DHEA-S exerted this effect by decreasing thrombin-dependent dense granule secretion, and so impairing the positive feed-back loop provided by ADP. Furthermore, DHEA-S inhibited thrombin-dependent activation of Akt, ERK1/2, and p38 MAP kinase. Although both DHEA-S and DHEA directly activated in platelets the inhibitory cGMP/PGK/VASP pathway, these events were not responsible for the inhibitory action of DHEA-S in platelets. In addition DHEA-S acted in synergism with nitric oxide in inhibiting platelet aggregation. In conclusion DHEA-S inhibited platelet activation caused by a mild stimulus without completely hampering platelet functionality and thus DHEA-S may participate in the physiological mechanisms that maintain circulating platelets in a resting state. The role played by DHEA-S could be relevant mainly when the functionality of the vascular endothelium is compromised.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Piemonte Orientale A. Avogadro, Novara, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bertoni
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rastoldo
authors.forename: Chiara
authors.initials: C
authors.lastname: Sarasso
authors.forename: Clara
authors.initials: C
authors.lastname: Di Vito
authors.forename: Sara
authors.initials: S
authors.lastname: Sampietro
authors.forename: Michela
authors.initials: M
authors.lastname: Nalin
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bagarotti
authors.forename: Fabiola
authors.initials: F
authors.lastname: Sinigaglia
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015151:Immunoblotting; D020935:MAP Kinase Signaling System; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology
chemical_list: D010975:Platelet Aggregation Inhibitors; D009569:Nitric Oxide; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D000255:Adenosine Triphosphate; D013917:Thrombin