TY - JOUR
T1 - A noble function of BAY 11-7082
T2 - Inhibition of platelet aggregation mediated by an elevated cAMP-induced VASP, and decreased ERK2/JNK1 phosphorylations
AU - Lee, Hyun Sub
AU - Kim, Sung Dae
AU - Lee, Whi Min
AU - Endale, Mehari
AU - Kamruzzaman, S. M.
AU - Oh, Won Jun
AU - Cho, Jae Youl
AU - Kim, Sang Keun
AU - Cho, Hyun Jeong
AU - Park, Hwa Jin
AU - Rhee, Man Hee
PY - 2010/2/10
Y1 - 2010/2/10
N2 - Platelets, though anucleated, possess several transcription factors, including NF-κB, that exert non-genomic functions regulating platelet activation. Since platelets have not only been recognized as central players of homeostasis, but also participated in pathological conditions such as thrombosis, atherosclerosis, and inflammation, we examined rat platelet NF-κB expression and evaluated the effects of anti-inflammatory drug BAY 11-7082, an inhibitor of NF-κB activation, in platelet physiology. Western blotting revealed that rat platelets express NF-κB. BAY 11-7082, dose dependently, inhibited collagen- or thrombin-induced-platelet aggregation. ATP release, TXB2 formation, P-selectin expression, and intercellular Ca2+ concentration activated by collagen were reduced in BAY 11-7082-treated platelets. BAY 11-7082 elevated intracellular levels of cAMP, but not cGMP, and its co-incubation with cAMP-activating agent (forskolin) or its hydrolyzing enzyme inhibitor (3-isobutyl-1-methylxanthine, IBMX), synergistically inhibited collagen-induced-platelet aggregation. In addition, vasodilator-stimulated-phosphoprotein (VASP) phosphorylation was enhanced in BAY 11-7082-treated platelets, which was partially inhibited by a protein kinase A (PKA) inhibitor, H-89. Moreover, while p38 mitogen-activated protein kinase (MAPK) was not affected, BAY 11-7082 attenuated c-Jun N-terminal kinase 1 (JNK1) and extracellular-signal-regulated protein kinase 2 (ERK2) phosphorylations. In conclusion, BAY 11-7082 inhibits platelet activation, granule secretion, and aggregation, and that this effect is mediated by inhibition of JNK1 and ERK2 phosphorylations, and partially by stimulation of cAMP-dependent PKA VASP phosphorylation. The ability of BAY 11-7082 to inhibit platelet function might be relevant in cases involving aberrant platelet activation where the drug is considered as anti-atherothrombosis, and anti-inflammatory therapy.
AB - Platelets, though anucleated, possess several transcription factors, including NF-κB, that exert non-genomic functions regulating platelet activation. Since platelets have not only been recognized as central players of homeostasis, but also participated in pathological conditions such as thrombosis, atherosclerosis, and inflammation, we examined rat platelet NF-κB expression and evaluated the effects of anti-inflammatory drug BAY 11-7082, an inhibitor of NF-κB activation, in platelet physiology. Western blotting revealed that rat platelets express NF-κB. BAY 11-7082, dose dependently, inhibited collagen- or thrombin-induced-platelet aggregation. ATP release, TXB2 formation, P-selectin expression, and intercellular Ca2+ concentration activated by collagen were reduced in BAY 11-7082-treated platelets. BAY 11-7082 elevated intracellular levels of cAMP, but not cGMP, and its co-incubation with cAMP-activating agent (forskolin) or its hydrolyzing enzyme inhibitor (3-isobutyl-1-methylxanthine, IBMX), synergistically inhibited collagen-induced-platelet aggregation. In addition, vasodilator-stimulated-phosphoprotein (VASP) phosphorylation was enhanced in BAY 11-7082-treated platelets, which was partially inhibited by a protein kinase A (PKA) inhibitor, H-89. Moreover, while p38 mitogen-activated protein kinase (MAPK) was not affected, BAY 11-7082 attenuated c-Jun N-terminal kinase 1 (JNK1) and extracellular-signal-regulated protein kinase 2 (ERK2) phosphorylations. In conclusion, BAY 11-7082 inhibits platelet activation, granule secretion, and aggregation, and that this effect is mediated by inhibition of JNK1 and ERK2 phosphorylations, and partially by stimulation of cAMP-dependent PKA VASP phosphorylation. The ability of BAY 11-7082 to inhibit platelet function might be relevant in cases involving aberrant platelet activation where the drug is considered as anti-atherothrombosis, and anti-inflammatory therapy.
KW - BAY 11-7082
KW - cAMP
KW - MAP kinase
KW - Platelet
KW - TXA
KW - VASP
UR - http://www.scopus.com/inward/record.url?scp=73449084397&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2009.11.005
DO - 10.1016/j.ejphar.2009.11.005
M3 - Article
C2 - 19913011
AN - SCOPUS:73449084397
SN - 0014-2999
VL - 627
SP - 85
EP - 91
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -