PMID- 30359790
OWN - NLM
STAT- MEDLINE
DCOM- 20190114
LR  - 20190114
IS  - 1879-2472 (Electronic)
IS  - 0049-3848 (Linking)
VI  - 172
DP  - 2018 Dec
TI  - Platelet activity is negatively modulated by tumor necrosis factor alpha through 
      reductions of cytosolic calcium levels and integrin alphaIIbbeta3 
      phosphorylation.
PG  - 44-50
LID - S0049-3848(18)30563-2 [pii]
LID - 10.1016/j.thromres.2018.10.008 [doi]
AB  - INTRODUCTION: Tumor necrosis factor-alpha (TNF-alpha) exerts a critical role in 
      inflammatory events through two distinct receptors, TNFR1 and TNFR2. Platelets 
      have been recognized as important inflammatory cells, but little is known about 
      the effects of TNF-alpha on the platelet activity. OBJECTIVES: In the present study 
      we have studied the role of TNF-alpha on ADP-induced platelet aggregation and its 
      downstream signaling (c-Src and fibrinogen receptor phosphorylation, cytosolic 
      Ca(2+) mobilization, cAMP and cGMP levels and cell viability). METHODS AND 
      RESULTS: Washed rat platelets were incubated with TNF-alpha (1-3000 pg/ml) for 
      different time-periods (5-60 min) before the addition of ADP (5 muM) to induce 
      platelet aggregation. TNF-alpha concentration- and time-dependently inhibits 
      ADP-induced aggregation, which was significantly prevented by incubation with the 
      non-selective TNF-alpha receptor antagonist R7050. TNF-alpha (300 pg/ml, 30 min) 
      decreases thrombin-induced elevation of cytosolic Ca(++) levels by 2.2- fold 
      compared to untreated platelets. TNF-alpha decreases the cAMP levels, while 
      significantly increases the intracellular cyclic cGMP levels. However, the 
      pre-incubation of platelets with the guanylyl cyclase inhibitor ODQ, despite 
      decreasing the cGMP levels, does not modify the inhibitory effect of TNF-alpha on 
      ADP-induced platelet aggregation. Additionally, western blotting analysis showed 
      that TNF-alpha significantly reduced (Tyr 416)-c-Src and (Tyr773)-beta3 subunit of 
      alphaIIbbeta3 integrin phosphorylation. TNF-alpha does not affect the platelet viability in 
      any condition tested. CONCLUSION: Therefore, our results show that TNF-alpha 
      negatively modulates ADP-induced aggregation via TNFR1/TNFR2 receptors by 
      reducing cytosolic Ca(++) levels and by inhibiting c-Src and fibrinogen receptor 
      activation, which take place through cAMP- and cGMP-independent mechanisms.
CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
FAU - Bonfitto, Pedro H L
AU  - Bonfitto PHL
AD  - Department of Pharmacology, Faculty of Medical Sciences, University of Campinas 
      (UNICAMP), Campinas, SP, Brazil.
FAU - Naime, Ana C Antunes
AU  - Naime ACA
AD  - Department of Pharmacology, Faculty of Medical Sciences, University of Campinas 
      (UNICAMP), Campinas, SP, Brazil.
FAU - Lopes-Pires, M Elisa
AU  - Lopes-Pires ME
AD  - Department of Pharmacology, Faculty of Medical Sciences, University of Campinas 
      (UNICAMP), Campinas, SP, Brazil.
FAU - Goulart, Gisele
AU  - Goulart G
AD  - Department of Pharmacology, Faculty of Medical Sciences, University of Campinas 
      (UNICAMP), Campinas, SP, Brazil.
FAU - Mendes-Silverio, Camila B
AU  - Mendes-Silverio CB
AD  - Department of Pharmacology, Faculty of Medical Sciences, University of Campinas 
      (UNICAMP), Campinas, SP, Brazil.
FAU - Bueno, Paulo I
AU  - Bueno PI
AD  - Department of Pharmacology, Faculty of Medical Sciences, University of Campinas 
      (UNICAMP), Campinas, SP, Brazil.
FAU - Castilho, Roger F
AU  - Castilho RF
AD  - Department of Clinical Pathology, Faculty of Medical Sciences, University of 
      Campinas (UNICAMP), Campinas, SP, Brazil.
FAU - Antunes, Edson
AU  - Antunes E
AD  - Department of Pharmacology, Faculty of Medical Sciences, University of Campinas 
      (UNICAMP), Campinas, SP, Brazil.
FAU - Marcondes, Sisi
AU  - Marcondes S
AD  - Department of Pharmacology, Faculty of Medical Sciences, University of Campinas 
      (UNICAMP), Campinas, SP, Brazil. Electronic address: sisimp@fcm.unicamp.br.
LA  - eng
PT  - Journal Article
DEP - 20181009
PL  - United States
TA  - Thromb Res
JT  - Thrombosis research
JID - 0326377
RN  - 0 (Integrin beta3)
RN  - 0 (Platelet Glycoprotein GPIIb-IIIa Complex)
RN  - 0 (Platelet Membrane Glycoprotein IIb)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - H2D2X058MU (Cyclic GMP)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Blood Platelets/cytology/*metabolism
MH  - Calcium/*metabolism
MH  - Cyclic GMP/metabolism
MH  - Cytosol/metabolism
MH  - Integrin beta3/*metabolism
MH  - Male
MH  - Phosphorylation
MH  - *Platelet Aggregation
MH  - Platelet Glycoprotein GPIIb-IIIa Complex/*metabolism
MH  - Platelet Membrane Glycoprotein IIb/*metabolism
MH  - Rats, Wistar
MH  - Tumor Necrosis Factor-alpha/*metabolism
OTO - NOTNLM
OT  - C-Src
OT  - Calcium mobilization
OT  - Cyclic GMP
OT  - Integrin alphaIIbbeta3
OT  - Platelet aggregation
EDAT- 2018/10/26 06:00
MHDA- 2019/01/15 06:00
CRDT- 2018/10/26 06:00
PHST- 2018/04/12 00:00 [received]
PHST- 2018/09/12 00:00 [revised]
PHST- 2018/10/08 00:00 [accepted]
PHST- 2018/10/26 06:00 [pubmed]
PHST- 2019/01/15 06:00 [medline]
PHST- 2018/10/26 06:00 [entrez]
AID - S0049-3848(18)30563-2 [pii]
AID - 10.1016/j.thromres.2018.10.008 [doi]
PST - ppublish
SO  - Thromb Res. 2018 Dec;172:44-50. doi: 10.1016/j.thromres.2018.10.008. Epub 2018 
      Oct 9.