Suppression of early growth response factor-1 with egr-1 antisense oligodeoxynucleotide aggravates experimental duodenal ulcers.
Previously, we demonstrated that cysteamine releases endothelin-1 in the rat duodenal mucosa, followed by increased expression of 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 oligonucleotide 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 oligonucleotide 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 blot analysis were used to assess the expression of Egr-1 mRNA and protein as well as ERK, bFGF, PDGF, and VEGF. The antisense Egr-1 oligonucleotide inhibited the expression of egr-1 mRNA and protein and increased the duodenal ulcer size from 8.1 +/- 1.8 mm(2) in controls to 20.7 +/- 4.0 mm(2) (P < 0.01). Cysteamine induced phosphorylation of ERK1/2 and enhanced the synthesis of bFGF, PDGF, and VEGF in the preulcerogenic stages of duodenal ulceration, whereas egr-1 antisense oligonucleotide markedly decreased the expression of these growth factors in the duodenal mucosa. We also demonstrated that Egr-1 expression relates to the ulcerogenic effect of cysteamine because 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 experimental duodenal ulcers, most likely through the transcriptional inhibition of bFGF, PDGF, and VEGF synthesis.
Diagnostic and Molecular Medicine Health Care Group, Veterans Affairs Medical Center, Long Beach, CA 90822-5201, USA.
Tetyana
T
Khomenko
Sandor
S
Szabo
Xiaoming
X
Deng
Martin R
MR
Jadus
Hideki
H
Ishikawa
Klara
K
Osapay
Zsuzsa
Z
Sandor
Longchuan
L
Chen
D000818:Animals; D004195:Disease Models, Animal; D004381:Duodenal Ulcer / Q000378:metabolism* / Q000473:pathology*; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013489:Suppression, Genetic
D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D020319:Oligodeoxyribonucleotides, Antisense