Cysteamine alters redox state, HIF-1alpha transcriptional interactions and reduces duodenal mucosal oxygenation: novel insight into the mechanisms of duodenal ulceration.
Our recent studies demonstrated a critical role of enhanced transcriptional activity of early growth response factor-1 (Egr-1) in early stages of cysteamine-induced duodenal ulcer in rats. Since cysteamine is also a reducing agent, the aims of this study were to determine the effect of cysteamine on proximal duodenal mucosa: (a) redox status, (b) mucosal oxygenation, (c) expression of hypoxia-inducible factor 1 (HIF-1alpha) and its binding to DNA, and (d) HIF-1alpha interaction with Egr-1 and other redox-sensitive transcription factors. Here we demonstrate for the first time that cysteamine treatment reduced the duodenal oxygenation by 19% (vs. baseline) and markedly increased the redox status in duodenal mucosa (p<0.05). Cysteamine increased HIF-1alpha expression, its binding to DNA, and enhanced the HIF-1alpha interactions with Egr-1 and other transcription factors (e.g., AP-1, AP-2, L-III BP, NF-E1, NF-E2, STAT4, and MRE), their binding to DNA. Thus, these data demonstrate the involvement of the redox-dependent regulatory mechanisms in the early stages of duodenal ulceration.
Khomenko
Tetyana
T
Pathology and Laboratory Medicine Service, Diagnostic and Molecular Medicine Health Care Group, Department of Medicine, VA Medical Center, CA 90822, USA.
Deng
Xiaoming
X
Sandor
Zsuzsanna
Z
Tarnawski
Andrzej S
AS
Szabo
Sandor
S
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003543:Cysteamine / Q000494:pharmacology*; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004381:Duodenal Ulcer / Q000378:metabolism*; D004386:Duodenum / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects* / Q000502:physiology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D003543:Cysteamine; D004247:DNA