PMID- 28775078
OWN - NLM
STAT- MEDLINE
DCOM- 20171010
LR  - 20181113
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Print)
IS  - 0009-7330 (Linking)
VI  - 121
IP  - 8
DP  - 2017 Sep 29
TI  - TLR2 Plays a Key Role in Platelet Hyperreactivity and Accelerated Thrombosis 
      Associated With Hyperlipidemia.
PG  - 951-962
LID - 10.1161/CIRCRESAHA.117.311069 [doi]
AB  - RATIONALE: Platelet hyperreactivity, which is common in many pathological 
      conditions, is associated with increased atherothrombotic risk. The mechanisms 
      leading to platelet hyperreactivity are complex and not yet fully understood. 
      OBJECTIVE: Platelet hyperreactivity and accelerated thrombosis, specifically in 
      dyslipidemia, have been mechanistically linked to the accumulation in the 
      circulation of a specific group of oxidized phospholipids (oxPC(CD36)) that are 
      ligands for the platelet pattern recognition receptor CD36. In the current 
      article, we tested whether the platelet innate immune system contributes to 
      responses to oxPC(CD36) and accelerated thrombosis observed in hyperlipidemia. 
      METHODS AND RESULTS: Using in vitro approaches, as well as platelets from mice 
      with genetic deletion of MyD88 (myeloid differentiation factor 88) or TLRs 
      (Toll-like receptors), we demonstrate that TLR2 and TLR6 are required for the 
      activation of human and murine platelets by oxPC(CD36). oxPC(CD36) induce 
      formation of CD36/TLR2/TLR6 complex in platelets and activate downstream 
      signaling via TIRAP (Toll-interleukin 1 receptor domain containing adaptor 
      protein)-MyD88-IRAK (interleukin-1 receptor-associated kinase)1/4-TRAF6 (TNF 
      receptor-associated factor 6), leading to integrin activation via the SFK (Src 
      family kinase)-Syk (spleen tyrosine kinase)-PLCgamma2 (phospholipase Cgamma2) pathway. 
      Intravital thrombosis studies using ApoE(-/-) mice with genetic deficiency of 
      TLR2 or TLR6 have demonstrated that oxPC(CD36) contribute to accelerated 
      thrombosis specifically in the setting of hyperlipidemia. CONCLUSIONS: Our 
      studies reveal that TLR2 plays a key role in platelet hyperreactivity and the 
      prothrombotic state in the setting of hyperlipidemia by sensing a wide range of 
      endogenous lipid peroxidation ligands and activating innate immune signaling 
      cascade in platelets.
CI  - (c) 2017 American Heart Association, Inc.
FAU - Biswas, Sudipta
AU  - Biswas S
AD  - From the Department of Molecular Cardiology, Cleveland Clinic, OH.
FAU - Zimman, Alejandro
AU  - Zimman A
AD  - From the Department of Molecular Cardiology, Cleveland Clinic, OH.
FAU - Gao, Detao
AU  - Gao D
AD  - From the Department of Molecular Cardiology, Cleveland Clinic, OH.
FAU - Byzova, Tatiana V
AU  - Byzova TV
AD  - From the Department of Molecular Cardiology, Cleveland Clinic, OH.
FAU - Podrez, Eugene A
AU  - Podrez EA
AD  - From the Department of Molecular Cardiology, Cleveland Clinic, OH. 
      podreze@ccf.org.
LA  - eng
GR  - P01 HL073311/HL/NHLBI NIH HHS/United States
GR  - R01 HL071625/HL/NHLBI NIH HHS/United States
GR  - R01 HL077213/HL/NHLBI NIH HHS/United States
GR  - R01 HL126738/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20170803
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Apolipoproteins E)
RN  - 0 (CD36 Antigens)
RN  - 0 (Myd88 protein, mouse)
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - 0 (Phospholipids)
RN  - 0 (TLR2 protein, human)
RN  - 0 (TLR6 protein, human)
RN  - 0 (Tlr2 protein, mouse)
RN  - 0 (Tlr6 protein, mouse)
RN  - 0 (Toll-Like Receptor 2)
RN  - 0 (Toll-Like Receptor 6)
SB  - IM
MH  - Animals
MH  - Apolipoproteins E/deficiency/genetics
MH  - Blood Platelets/immunology/*metabolism
MH  - CD36 Antigens/deficiency/genetics
MH  - Disease Models, Animal
MH  - Female
MH  - Genetic Predisposition to Disease
MH  - HEK293 Cells
MH  - Humans
MH  - Hyperlipidemias/blood/genetics/immunology/*metabolism
MH  - Immunity, Innate
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myeloid Differentiation Factor 88/deficiency/genetics
MH  - Oxidation-Reduction
MH  - Phenotype
MH  - Phospholipids/blood
MH  - *Platelet Activation
MH  - Signal Transduction
MH  - Thrombosis/blood/genetics/immunology/*metabolism
MH  - Toll-Like Receptor 2/deficiency/genetics/*metabolism
MH  - Toll-Like Receptor 6/deficiency/genetics/metabolism
MH  - Transfection
PMC - PMC5623081
MID - NIHMS898089
OTO - NOTNLM
OT  - TLR2
OT  - hyperlipidemia
OT  - innate immune system
OT  - platelets
OT  - thrombosis
COIS- DISCLOSURES The authors have no conflict of interest to disclose.
EDAT- 2017/08/05 06:00
MHDA- 2017/10/11 06:00
PMCR- 2018/09/29
CRDT- 2017/08/05 06:00
PHST- 2017/07/05 00:00 [received]
PHST- 2017/07/27 00:00 [revised]
PHST- 2017/08/03 00:00 [accepted]
PHST- 2017/08/05 06:00 [pubmed]
PHST- 2017/10/11 06:00 [medline]
PHST- 2017/08/05 06:00 [entrez]
PHST- 2018/09/29 00:00 [pmc-release]
AID - CIRCRESAHA.117.311069 [pii]
AID - 10.1161/CIRCRESAHA.117.311069 [doi]
PST - ppublish
SO  - Circ Res. 2017 Sep 29;121(8):951-962. doi: 10.1161/CIRCRESAHA.117.311069. Epub 
      2017 Aug 3.