Tranilast inhibits protein kinase C-dependent signalling pathway linked to angiogenic activities and gene expression of retinal microcapillary endothelial cells

Tranilast, first developed as an anti-allergic drug, has been reported to inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis and vasopermeability. To further clarify the inhibitory mechanism, we investigated the effects of tranilast on VEGF binding and subsequent intracellular signalling pathway linked to angiogenic activities and gene expression of bovine retinal microcapillary endothelial cells.

Tranilast significantly (P<0.01) inhibited VEGF, basic fibroblast growth factor (bFGF), and hypoxia conditioned media-induced BREC proliferation in a dose dependent manner with IC₅₀'s of 22, 82 and 10 μM, respectively.

VEGF-induced migration was also inhibited by tranilast in a dose dependent manner, with IC₅₀ of 18 μM, and complete inhibition was observed at 300 μM (P<0.01). Tranilast suppressed VEGF-induced tube formation in a dose dependent manner with maximum (46%) inhibition observed at 300 μM (P<0.05).

Tranilast inhibited phorbol myristate acetate (PMA)-dependent stimulation of [^{H]-thymidine incorporation and VEGF- and PMA-induced gene expression of integrin αv and c-}fos in BREC.

Tranilast suppressed VEGF- and PMA-stimulated PKC activity in BREC.

Tranilast did not affect VEGF binding or VEGF-induced phosphorylation of tyrosine residues of VEGF receptor- and phospholipase Cγ and their associated proteins.

These data suggest that tranilast might prove an effective inhibitor to prevent retinal neovascularization in ischaemic retinal diseases, and that its inhibitory effect might be through suppression of PKC-dependent signal transduction in BREC.