Potent inhibition of human platelets by cGMP analogs independent of cGMP-dependent protein kinase.
Platelets play a key role in hemostasis through their ability to rapidly adhere to activated or injured endothelium, subendothelial matrix proteins, and other activated platelets. A strong equilibrium between activating and inhibiting processes is essential for normal platelet and vascular function, impairment of this equilibrium being associated with either thrombophilic or bleeding disorders. Both cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) have been established as crucial and synergistic intracellular messengers that mediate the effects of platelet inhibitors such as nitric oxide (NO) and prostacyclin (PG-I2). However, it was recently suggested that a rapid cGMP/cGMP-dependent protein kinase (cGK)-mediated extracellular signal-related kinase (ERK) phosphorylation promotes platelet activation. This hypothesis was examined here by evaluating established and proposed cGK activators/inhibitors with respect to their capacity to promote either platelet activation or inhibition. In particular, the regulatory role of cGK for ERK phosphorylation and thrombin-, thromboxane-, and VWF-induced platelet activation was investigated. The data obtained do not support the concept that cGK-mediated ERK phosphorylation promotes platelet activation but confirm the inhibitory role of cGK in platelet function. One explanation for these discrepancies is the novel finding that extracellular cGMP analogs potently and rapidly inhibit thrombin-, thromboxane-, and VWF-induced human platelet signaling and activation by a cGK-independent mechanism.
Gambaryan
Stepan
S
Institute of Clinical Biochemistry and Pathobiochemistry, University of Wuerzburg, Germany.
Geiger
Jörg
J
Schwarz
Ulrike R
UR
Butt
Elke
E
Begonja
Antonija
A
Obergfell
Achim
A
Walter
Ulrich
U
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D002118:Calcium / Q000097:blood; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000097:blood*; D006801:Humans; D007700:Kinetics; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D014841:von Willebrand Factor / Q000494:pharmacology
D020030:Nitric Oxide Donors; D010975:Platelet Aggregation Inhibitors; D014841:von Willebrand Factor; D015124:8-Bromo Cyclic Adenosine Monophosphate; C016276:8-bromocyclic GMP; D026423:S-Nitroso-N-Acetylpenicillamine; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; D002118:Calcium