PMID- 10613665
OWN - NLM
STAT- MEDLINE
DCOM- 20000131
LR  - 20091119
IS  - 0340-6245 (Print)
IS  - 0340-6245 (Linking)
VI  - 82
IP  - 6
DP  - 1999 Dec
TI  - Early platelet activation by low density lipoprotein via p38MAP kinase.
PG  - 1749-56
AB  - Low Density Lipoprotein (LDL) is known to sensitize platelets for physiological
      agonists. To clarify the basis of this sensitization, we investigated the
      involvement of p38MAP Kinase (p38MAPK). As dual phosphorylation on Thr180 and
      Tyr182 of p38MAPK is the trigger for activation of the kinase, p38MAPK-activity
      was measured with an antibody that recognizes the dual-phosphorylated sequence.
      LDL induced a rapid and dose dependent activation of p38MAPK. The activation was 
      not inhibited by a wide variety of inhibitors of platelet signalling, including
      TxA2-formation, Phospholipase C-activation, Ca2+-mobilization and ERK
      1/2-activation. Only a slight reduction in p38MAPK-activation was observed when
      protein kinase C was inhibited. Activation of p38MAPK was strongly inhibited by a
      rise in cAMP. Thus, p38MAPK-activation was upstream of most signalling pathways
      and close to the LDL-receptor. A number of platelet receptors was screened with
      the use of antibodies. Integrins alphaIIbbeta3 and alpha2beta1, as well as the
      FcgammaRII-receptor, CD36 (platelet glycoprotein IV), CD68 (gp110) and Low
      Density Lipoprotein-receptor related protein (LRP) were not implicated in
      LDL-induced p38MAPK-activation. Inhibition of LDL binding by modification of apo 
      B100 lysines reduced p38MAPK-activation by 80%. Activation of p38MAPK resulted in
      an increase in release of arachidonic acid, the precursor for thromboxane A2
      synthesis. In conclusion, activation of p38MAPK might be the first step in
      platelet sensitization by LDL, leading to formation of arachidonate metabolites
      and increased aggregation and secretion responses to physiological agonists.
FAU - Hackeng, C M
AU  - Hackeng CM
AD  - Department of Clinical Chemistry, University Hospital Utrecht, The Netherlands.
FAU - Relou, I A
AU  - Relou IA
FAU - Pladet, M W
AU  - Pladet MW
FAU - Gorter, G
AU  - Gorter G
FAU - van Rijn, H J
AU  - van Rijn HJ
FAU - Akkerman, J W
AU  - Akkerman JW
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Germany
TA  - Thromb Haemost
JT  - Thrombosis and haemostasis
JID - 7608063
RN  - 0 (Lipoproteins, LDL)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Humans
MH  - Lipoproteins, LDL/*pharmacology
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - Phosphorylation
MH  - Platelet Activation/*drug effects
MH  - Signal Transduction/*drug effects
MH  - p38 Mitogen-Activated Protein Kinases
EDAT- 1999/12/29 00:00
MHDA- 1999/12/29 00:01
CRDT- 1999/12/29 00:00
PHST- 1999/12/29 00:00 [pubmed]
PHST- 1999/12/29 00:01 [medline]
PHST- 1999/12/29 00:00 [entrez]
AID - 99121749 [pii]
PST - ppublish
SO  - Thromb Haemost. 1999 Dec;82(6):1749-56.