Previously we demonstrated that cysteamine releases endothelin-1 in the rat duodenal mucosa, followed by increased expression of the early growth response factor - 1 (egr-1). We hypothesized that egr-1 is a key mediator gene in the multifactorial mechanisms of duodenal ulcer development and healing because its protein, transcription factor product Egr-1 regulates the expression of angiogenic growth factors. We wanted to determine the effect of egr-1 antisense on cysteamine-induced duodenal ulcers, as well as on the expression of bFGF, PDGF and VEGF of which synthesis is modulated by Egr-1. An antisense to egr-1 was used to inhibit the synthesis of Egr-1 and to determine its effect on ulcer formation in the rat model of cysteamine-induced duodenal ulceration. Real-time RT-PCR and Western blotting were used to assess the expression of egr-1 mRNA, Egr-1 protein as well as ERK, bFGF, PDGF and VEGF. The antisense egr-1 inhibited the expression of egr-1 mRNA and Egr-1 protein, and increased the duodenal ulcer size from 8.1±1.8 in controls to 20.7±4.0 mm² (p<0.01). Cysteamine induced phosphorylation of both ERK1/2, enhanced the synthesis of bFGF, PDGF and VEGF in the pre-ulcerogenic stages of duodenal ulceration while the egr-1 antisense markedly decreased the expression of these growth factors in the duodenal mucosa. We also demonstrated that the Egr-1 expression relates to the ulcerogenic effect of cysteamine since these actions were not exerted by the toxic analog ethanolamine. Thus, Egr-1 seems to play a critical role in duodenal ulceration because Egr-1 downregulation aggravates the experimental duodenal ulcers, most likely through the transcriptional inhibition of bFGF, PDGF and VEGF synthesis.