Cyclooxygenase gene expression is down-regulated by heparin-binding (acidic fibroblast) growth factor-1 in human endothelial cells

Abstract

The expression of cyclooxygenase (EC 1.14.99.1, Cox), a rate-limiting enzyme in the biosynthesis of inflammatory prostanoids, is regulated by growth factors and cytokines. We have shown previously that the cytokine interleukin-1, an inhibitor of endothelial growth in vitro and stimulator of prostacyclin production, induces the expression of the 3-kilobase Cox transcript in cultured human umbilical vein endothelial cells (HUVEC). In contrast, the endothelial cell mitogen, heparin-binding (acidic fibroblast) growth factor-1 (HBGF-1) inhibits the synthesis of prostacyclin in HUVEC. In this report, we describe the effect of HBGF-1 on Cox mRNA expression in HUVEC. Cells cultured in the presence of HBGF-1 express diminished Cox mRNA levels whereas quiescent cells maintained in serum expressed a 7-fold higher level of the transcript for Cox. Concomitantly, the level of the Cox translation product and prostacyclin synthesis are also reduced by HBGF-1. Further, HBGF-1, in the presence of heparin, down-regulates the levels of the Cox transcript in a dose- and time-dependent manner. The onset of action of HBGF-1 is slow, requiring up to 24 h to depress the level of Cox mRNA. Lastly, the effective dose of HBGF-1 to depress Cox mRNA levels is similar to that required for mitogenesis, suggesting that cell proliferation may be required for the reduction of Cox expression in vitro. Thus, Cox may belong to a class of genes that are reversibly down-regulated during periods of endothelial cell proliferation.