Effect of parathyroid-hormone-related protein on human platelet activation

Arantxa Ortega , Mª Teresa Pérez de Prada , Petra J Mateos-Cáceres , Priscila Ramos Mozo , Juan J González-Armengol , Juan M González del Castillo , Javier Martín Sánchez , Pedro Villarroel , José L Santiago , Ricardo J Bosch , Carlos Macaya , Pedro Esbrit , Antonio J López-Farré (1)

1 Cardiovascular Research Unit

Recent evidence suggests that parathyroid hormone (PTH)-related protein (PTHrP) can act as an inflammatory mediator in several pathological settings including cardiovascular disease. This study was to determine whether PTHrP might be involved in human platelet activation. We used a turbidimetric method to determine platelet aggregation. The expression of the PTH type 1 receptor (PTH1R) in human platelets was analyzed by Western blot and flow cytometry analysis. PTHrP (1-36) (10 -7} mol L -1}) by itself failed to modify the activation of platelets. However, it significantly enhanced ADP-induced platelet activation, and also increased the ability of other agonists (thrombin, collagen and arachidonic acid) to induce platelet aggregation. H89 (10 -6} mol L -1}) and Rp-cAMPS (25 × 10 -6} mol L -1}), two protein kinase (PK) A inhibitors, and bisindolylmaleimide I (25 × 10 -9} mol L -1}), a PKC inhibitor, partially decreased the promoting effect of PTHrP (1-36) on ADP-induced platelet activation. Meanwhile, PTHrP (7-34) (10 -6} mol L -1}), a PTH1R antagonist, as well as PD098059 (10 -5} mol L -1}), a mitogen-activated protein kinase (MAPK) inhibitor, or a farnesyltransferase inhibitor abolished this effect of PTHrP (1-36). Moreover, PTHrP (1-36) (10 -7} mol L -1}) increased (2-fold over control) MAPK activation in human platelets. The PTH1R was detected in platelets, and the number of platelets expressing it on their surface in patients during an acute myocardial infarction (AMI) was not different from that in a group of patients with similar cardiovascular risk factors without AMI. Western blot analysis showed that the total PTH1R protein levels were markedly higher in platelets from control than those from AMI patients. PTH1R was found in plasma, where its levels were increased in AMI patients compared with controls. In conclusion, human platelets express the PTH1R. PTHrP can interact with this receptor to enhance human platelet activation induced by several agonists through a MAPK-dependent mechanism.

Mots clés: Medicine

Arantxa Ortega, Mª Teresa Pérez de Prada, Petra J Mateos-Cáceres, Priscila Ramos Mozo, Juan J González-Armengol, et al.. Effect of parathyroid-hormone-related protein on human platelet activation. Clinical Science, 2007, 113 (7), pp.319-327. ⟨10.1042/CS20070010⟩. ⟨hal-00479361⟩