Affiliation:
1. From the Laboratoires Glaxo, Centre de Recherches, ZA de Courtaboeuf, Les Ulis, France.
Abstract
Abstract
The in vitro effects of retinoids on fibrinogen synthesis were investigated in HepG2 cells and primary human hepatocytes. In vivo effects were studied in the rat. In HepG2 cells, maximal stimulation (twofold) of fibrinogen secretion was obtained when cells were incubated in the presence of 1 μmol/L all-
trans
retinoic acid (T-RA) for 24 hours. A comparable increase was observed for both de novo fibrinogen synthesis and fibrinogen β chain mRNA level. In primary cultures of human hepatocytes, treatment with 1 μmol/L T-RA for 72 hours also gave a twofold increase in fibrinogen production. Furthermore, rats treated for 6 days with 100 mg · kg
−1
· d
−1
T-RA presented increased fibrinogen plasma levels (110%). A selective retinoic X receptor (RXR) agonist, 4-[1-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzoic acid (3-methyl TTNEB), as well as 9-
cis
retinoic acid, a natural RXR ligand, mimicked the effects of T-RA on fibrinogen synthesis in vitro at lower concentrations. In contrast, a selective retinoic A receptor α (RARα) agonist was a poor activator. The ED
50
of the different retinoids on fibrinogen secretion by HepG2 cells was 25 nmol/L for T-RA, 4 nmol/L for 9-
cis
retinoic acid, 11 nmol/L for the synthetic RXR agonist, and >500 nmol/L for the RARα agonist. However, incubation of HepG2 cells with RXR agonist together with RARα agonist resulted in a further increase in fibrinogen production. The secretion of two other acute-phase proteins, α-antichymotrypsin and caeruloplasmin, was also stimulated by retinoids in HepG2 cells but by a different regulatory mechanism. We conclude that activation of RXR by a specific ligand upregulates fibrinogen production by hepatocytes. Elevated levels of fibrinogen in rats treated with T-RA indicate that retinoids may be involved in the physiological regulation of fibrinogen, with a key role for RXR.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
10 articles.
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