Coagulation factor XI induces Ca2+response and accelerates cell migration in vascular smooth muscle cells via proteinase-activated receptor 1
| Autor: | Katsuya Hirano, Tetsuo Yamashita, Wenhua Liu, Takeshi Hashimoto |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Vascular smooth muscle Physiology Chemistry Activated coagulation factor Cell migration Cell Biology 030204 cardiovascular system & hematology Cell biology Serine 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Coagulation Coagulation factor XI Proteinase Activated Receptor 1 |
| Zdroj: | American Journal of Physiology-Cell Physiology. 316:C377-C392 |
| ISSN: | 1522-1563 0363-6143 |
| DOI: | 10.1152/ajpcell.00426.2018 |
| Popis: | 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 PAR1at the same site (R45/S46) as that of thrombin, a canonical PAR1agonist. 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. |
| Databáze: | OpenAIRE |
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