Phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) by the anti-platelet drug, cilostazol, in platelets

Vasodilator-stimulated phosphoprotein (VASP) is a regulator of actin dynamics in platelets and a common substrate of both cAMP- and cGMP-dependent protein kinases (PKA and PKG). Elevations of the cAMP and cGMP concentration have been shown to inhibit platelet aggregation. Intracellular levels of cAM...

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Bibliographic Details
Published in:Platelets (Edinburgh) 2003-09, Vol.14 (6), p.381-390
Main Authors: Sudo, Toshiki, Ito, Hideki, Kimura, Yukio
Format: Article
Language:English
Subjects:
Adenine - analogs & derivatives
Adenine - pharmacology
Adenylyl Cyclases - blood
Blood Proteins - drug effects
Blood Proteins - metabolism
Cell Adhesion Molecules - blood
Cell Adhesion Molecules - drug effects
Colforsin - pharmacology
Cyclic AMP - blood
Cyclic AMP-Dependent Protein Kinases - blood
Enzyme Activation
Enzyme Inhibitors - pharmacology
Humans
Isoquinolines - pharmacology
Kinetics
Microfilament Proteins
Nitroprusside - pharmacology
Phosphodiesterase Inhibitors - pharmacology
Phosphoproteins - blood
Phosphoproteins - drug effects
Phosphorylation
Platelet Aggregation Inhibitors - pharmacology
Sulfonamides
Tetrazoles - pharmacology
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Summary:Vasodilator-stimulated phosphoprotein (VASP) is a regulator of actin dynamics in platelets and a common substrate of both cAMP- and cGMP-dependent protein kinases (PKA and PKG). Elevations of the cAMP and cGMP concentration have been shown to inhibit platelet aggregation. Intracellular levels of cAMP and cGMP are regulated by the synthesizing system of adenylate cyclases, and hydrolysis by cyclic nucleotide phosphodiesterases (PDEs). The present study examined the effect of the anti-platelet drug, cilostazol, which inhibits PDE3 activity, on VASP phosphorylation in platelets. VASP phosphorylation was examined by immunoblotting with an anti-VASP antibody, M4, and an anti-phospho-VASP antibody, 16C2. Cilostazol phosphorylated VASP at both Ser157 and Ser239 in a concentration-dependent manner, but EHNA (PDE2 inhibitor), dipyridamole and zaprinast (PDE5 inhibitors) did not. Forskolin (adenylate cyclase activator) and sodium nitroprusside (SNP, NO donor) resulted in the VASP phosphorylation, with increase in the cAMP and cGMP level, respectively. Cilostazol increased cAMP, but not cGMP levels, in platelets. EHNA, zaprinast and dipyridamole, had no effect on cAMP and cGMP levels. The PKA PKG inhibitor, H-89, inhibited VASP phosphorylation by cilostazol. These results demonstrated that cilostazol phosphorylates VASP through the PDE3 inhibition, increase of cAMP level, and PKA activation in platelets.
ISSN:0953-7104
1369-1635
DOI:10.1080/09537100310001598819