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A noble function of BAY 11-7082: Inhibition of platelet aggregation mediated by an elevated cAMP-induced VASP, and decreased ERK2/JNK1 phosphorylations.
Eur J Pharmacol. 2010 Feb 10; 627(1-3):85-91.EJ

Abstract

Platelets, though anucleated, possess several transcription factors, including NF-kappaB, 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-kappaB expression and evaluated the effects of anti-inflammatory drug BAY 11-7082, an inhibitor of NF-kappaB activation, in platelet physiology. Western blotting revealed that rat platelets express NF-kappaB. BAY 11-7082, dose dependently, inhibited collagen- or thrombin-induced-platelet aggregation. ATP release, TXB(2) formation, P-selectin expression, and intercellular Ca(2+) 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.

Authors+Show Affiliations

College of Biomedical Science and Engineering, and Regional Research Center, Inje University, Gimhae 200-701, Republic of Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19913011

Citation

Lee, Hyun-Sub, et al. "A Noble Function of BAY 11-7082: Inhibition of Platelet Aggregation Mediated By an Elevated cAMP-induced VASP, and Decreased ERK2/JNK1 Phosphorylations." European Journal of Pharmacology, vol. 627, no. 1-3, 2010, pp. 85-91.
Lee HS, Kim SD, Lee WM, et al. A noble function of BAY 11-7082: Inhibition of platelet aggregation mediated by an elevated cAMP-induced VASP, and decreased ERK2/JNK1 phosphorylations. Eur J Pharmacol. 2010;627(1-3):85-91.
Lee, H. S., Kim, S. D., Lee, W. M., Endale, M., Kamruzzaman, S. M., Oh, W. J., Cho, J. Y., Kim, S. K., Cho, H. J., Park, H. J., & Rhee, M. H. (2010). A noble function of BAY 11-7082: Inhibition of platelet aggregation mediated by an elevated cAMP-induced VASP, and decreased ERK2/JNK1 phosphorylations. European Journal of Pharmacology, 627(1-3), 85-91. https://doi.org/10.1016/j.ejphar.2009.11.005
Lee HS, et al. A Noble Function of BAY 11-7082: Inhibition of Platelet Aggregation Mediated By an Elevated cAMP-induced VASP, and Decreased ERK2/JNK1 Phosphorylations. Eur J Pharmacol. 2010 Feb 10;627(1-3):85-91. PubMed PMID: 19913011.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A noble function of BAY 11-7082: 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, Y1 - 2009/11/10/ PY - 2009/04/21/received PY - 2009/10/12/revised PY - 2009/11/03/accepted PY - 2009/11/17/entrez PY - 2009/11/17/pubmed PY - 2010/4/7/medline SP - 85 EP - 91 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 627 IS - 1-3 N2 - Platelets, though anucleated, possess several transcription factors, including NF-kappaB, 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-kappaB expression and evaluated the effects of anti-inflammatory drug BAY 11-7082, an inhibitor of NF-kappaB activation, in platelet physiology. Western blotting revealed that rat platelets express NF-kappaB. BAY 11-7082, dose dependently, inhibited collagen- or thrombin-induced-platelet aggregation. ATP release, TXB(2) formation, P-selectin expression, and intercellular Ca(2+) 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. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/19913011/A_noble_function_of_BAY_11_7082:_Inhibition_of_platelet_aggregation_mediated_by_an_elevated_cAMP_induced_VASP_and_decreased_ERK2/JNK1_phosphorylations_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(09)00999-6 DB - PRIME DP - Unbound Medicine ER -