Submitted on February 21, 2005
Accepted on February 9, 2006
Suppression of early growth response factor - 1 with egr-1 antisense oligodeoxynucleotide aggravates experimental duodenal ulcers
Tetyana Khomenko1, Sandor Szabo1*, Xiaoming Deng1, Martin R. Jadus1, Hideki Ishikawa1, Klara Osapay1, Zsuzsa Sandor1, and Longchuan Chen1
1 Diagnostic and Molecular Medicine Health Care Group, and Departments of Pathology and Pharmacology, VA Medical Center, Long Beach, University of California-Irvine, Long Beach, CA, USA
* To whom correspondence should be addressed. E-mail: sandor.szabo{at}med.va.gov.
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.
