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.
Khomenko
Tetyana
T
Diagnostic and Molecular Medicine Health Care Group, Veterans Affairs Medical Center, Long Beach, CA 90822-5201, USA.
Szabo
Sandor
S
Deng
Xiaoming
X
Jadus
Martin R
MR
Ishikawa
Hideki
H
Osapay
Klara
K
Sandor
Zsuzsa
Z
Chen
Longchuan
L
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