Coagulation factor XⅠinduces Ca2+ response and accelerates cell migration in vascular smooth muscle cells via proteinase-activated receptor 1

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URI http://shark.lib.kagawa-u.ac.jp/kuir/metadata/28677
Title
Coagulation factor XⅠinduces Ca2+ response and accelerates cell migration in vascular smooth muscle cells via proteinase-activated receptor 1
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Description

Abstract

Activated coagulation factor XI (FXIa) is a serine proteinase that plays a key role in the intrinsic coagulation pathway. The analysis of FXI-knockout mice has indicated the contribution of FXI to the pathogenesis of atherosclerosis. However, the underlying mechanism remains unknown. We hypothesized that FXIa exerts vascular smooth muscle effects via proteinase-activated receptor 1 (PAR1). Fura-2 fluorometry revealed that FXIa elicited intracellular Ca2+ signal in rat embryo aorta smooth muscle A7r5 cells. The influx of extracellular Ca2+ played a greater role in generating Ca2+ signal than the Ca2+ release from intracellular stores. The FXIa-induced Ca2+ signal was abolished by the pretreatment with atopaxar, an antagonist of PAR1, or 4-amidinophenylmethanesulfonyl fluoride (p-APMSF), an inhibitor of proteinase, while it was also lost in embryonic fibroblasts derived from PAR1-/- mice. FXIa cleaved the recombinant protein containing the extracellular region of PAR1 at the same site (R45/S46) as that of thrombin, a canonical PAR1 agonist. The FXIa-induced Ca2+ influx was inhibited by diltiazem, an L-type Ca2+ channel blocker, and by siRNA targeted to CaV1.2. The FXIa-induced Ca2+ influx was also inhibited by GF109203X and rottlerin, inhibitors of protein kinase C. In a wound healing assay, FXIa increased the rate of cell migration by 2.46-fold of control, which was partly inhibited by atopaxar or diltiazem. In conclusion, FXIa mainly elicits the Ca2+ signal via the PAR1/CaV1.2-mediated Ca2+ influx and accelerates the migration in vascular smooth muscle cells. The present study provides the first evidence that FXIa exerts a direct cellular effect on vascular smooth muscle.

KEYWORDS:

coagulation factor XI; proteinase-activated receptor; vascular smooth muscle

(医博甲714)

Author
著者 劉 文華
著者(ヨミ) リュウ ブンカ
著者(別表記) Liu Wenhua
Publication Title
American Journal of Physiology - Cell Physiology
Publication Title Alternative
Am J Physiol Cell Physiol.
Volume
316
Issue
3
Start Page
C377
End Page
C392
Publisher
American Physiological Society
Published Date
2018-12-19
ISSN
0363-6143
NCID
AA00521122
PMID
30566391
DOI
10.1152/ajpcell.00426.2018
Resource Type
Thesis or Dissertation
Language
eng
Relation
出版社版DOIリンク(URL): https://doi.org/10.1152/ajpcell.00426.2018
Resource URL
https://doi.org/10.1152/ajpcell.00426.2018
Text Version
ETD
Grant ID
博甲第714号
Grant Date
2019-03-24
Degree Name
博士(医学)
Grantor
香川大学
Set
香川大学
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