PMID- 27609643
OWN - NLM
STAT- MEDLINE
DCOM- 20170804
LR  - 20210202
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 128
IP  - 16
DP  - 2016 Oct 20
TI  - Platelet WDR1 suppresses platelet activity and is associated with cardiovascular 
      disease.
PG  - 2033-2042
LID - 10.1182/blood-2016-03-703157 [doi]
AB  - Platelet activity plays a major role in hemostasis with increased platelet 
      activity likely contributing to the pathogenesis of atherothrombosis. We sought 
      to identify associations between platelet activity variability and 
      platelet-related genes in healthy controls. Transcriptional profiling of 
      platelets revealed that WD-40 repeat domain 1 (WDR1), an enhancer of 
      actin-depolymerizing factor activity, is downregulated in platelet messenger RNA 
      (mRNA) from subjects with a hyperreactive platelet phenotype. We used the human 
      megakaryoblastic cell line MEG-01 as an in vitro model for human megakaryocytes 
      and platelets. Stimulation of MEG-01 with thrombin reduced levels of WDR1 
      transcripts and protein. WDR1 knockdown (KD) in MEG-01 cells increased adhesion 
      and spreading in both the basal and activated states, increased F-actin content, 
      and increased the basal intracellular calcium concentration. Platelet-like 
      particles (PLPs) produced by WDR1 KD cells were fewer in number but larger than 
      PLPs produced from unmodified MEG-01 cells, and had significantly increased 
      adhesion in the basal state and upon thrombin activation. In contrast, WDR1 
      overexpression reversed the WDR1 KD phenotype of megakaryocytes and PLPs. To 
      translate the clinical significance of these findings, WDR1 expression was 
      measured in platelet RNA from subjects with established cardiovascular disease (n 
      = 27) and age- and sex-matched controls (n = 10). The WDR1 mRNA and protein level 
      was significantly lower in subjects with cardiovascular disease. These data 
      suggest that WDR1 plays an important role in suppressing platelet activity, where 
      it alters the actin cytoskeleton dynamics, and downregulation of WDR1 may 
      contribute to the platelet-mediated pathogenesis of cardiovascular disease.
CI  - (c) 2016 by The American Society of Hematology.
FAU - Montenont, Emilie
AU  - Montenont E
AD  - Divisions of Cardiology and Hematology, Department of Medicine, New York 
      University School of Medicine, New York, NY.
FAU - Echagarruga, Christina
AU  - Echagarruga C
AD  - Divisions of Cardiology and Hematology, Department of Medicine, New York 
      University School of Medicine, New York, NY.
FAU - Allen, Nicole
AU  - Allen N
AD  - Divisions of Cardiology and Hematology, Department of Medicine, New York 
      University School of Medicine, New York, NY.
FAU - Araldi, Elisa
AU  - Araldi E
AD  - Section of Comparative Medicine and Department of Pathology, Yale University 
      School of Medicine, New Haven, CT; and.
FAU - Suarez, Yajaira
AU  - Suarez Y
AD  - Section of Comparative Medicine and Department of Pathology, Yale University 
      School of Medicine, New Haven, CT; and.
FAU - Berger, Jeffrey S
AU  - Berger JS
AD  - Divisions of Cardiology and Hematology, Department of Medicine, New York 
      University School of Medicine, New York, NY.
AD  - Division of Vascular Surgery, Department of Surgery, New York University School 
      of Medicine, New York, NY.
LA  - eng
GR  - P30 CA016359/CA/NCI NIH HHS/United States
GR  - R01 HL114978/HL/NHLBI NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160908
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Microfilament Proteins)
RN  - 0 (WDR1 protein, human)
SB  - IM
MH  - Adult
MH  - Atherosclerosis/genetics/*metabolism/pathology
MH  - Blood Platelets/*metabolism/pathology
MH  - Cell Line
MH  - Cytoskeleton/genetics/*metabolism/pathology
MH  - Female
MH  - *Gene Expression Regulation
MH  - Humans
MH  - Male
MH  - Megakaryocytes/metabolism/pathology
MH  - Microfilament Proteins/*biosynthesis/genetics
MH  - *Platelet Adhesiveness
PMC - PMC5073182
EDAT- 2016/09/10 06:00
MHDA- 2017/08/05 06:00
PMCR- 2017/10/20
CRDT- 2016/09/10 06:00
PHST- 2016/03/25 00:00 [received]
PHST- 2016/09/01 00:00 [accepted]
PHST- 2016/09/10 06:00 [pubmed]
PHST- 2017/08/05 06:00 [medline]
PHST- 2016/09/10 06:00 [entrez]
PHST- 2017/10/20 00:00 [pmc-release]
AID - S0006-4971(20)34030-1 [pii]
AID - 2016/703157 [pii]
AID - 10.1182/blood-2016-03-703157 [doi]
PST - ppublish
SO  - Blood. 2016 Oct 20;128(16):2033-2042. doi: 10.1182/blood-2016-03-703157. Epub 
      2016 Sep 8.