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Ann. N.Y. Acad. Sci., Annals PrePrint, published online ahead of print July 26, 2007 doi: 10.1196/annals.1391.033 Copyright © 2007 by the New York Academy of Sciences description
1 Diagnostic & Molecular Medicine Health Care, VA Long Beach Healthcare System, 5901 East 7th street, Long Beach, California, 90822, United States 2 Diagnostic & Molecular Medicine Health Care, VA Long Beach Healthcare System, 5901 East 7th street, Long Beach , California, 90822, United States 3 Department of Internal Medicine, VA Long Beach Healthcare System, 5901 East 7th Street, Long Beach , California, 90822, United States 4 Diagnostic & Molecular Medicine Health Care, VA Long Beach Healthcare System, 5901 East 7th Street, Long Beach , California, 90822, United States
* To whom correspondence should be addressed. E-mail: sandor.szabo{at}med.va.gov. PrePrint Abstract
Stress is a major etiologic factor in the pathogenesis of gastric & duodenal ulceration, as first described in rats by Hans Selye. In patients with "peptic ulcers" duodenal ulcers (DU) are more frequent than gastric ulcers (except in Japan). Thus, our research during the last 3 decades focused on the molecular mechanisms of DU in rodent models of chemically induced DU, and here we review our 3 recent findings: Endothelins (ET-1), the immediate early gene egr-1 & imbalance of angiogenic/anti-angiogenic molecules. Namely, we found an enhanced expression & release of ET-1 within 15-30 min after the administration of duodenal ulcerogen cysteamine, resulting in local ischemia that triggers the expression of hypoxia-inducible factors (HIF-1α). Our gene expression studies also revealed an early (0.5-2 hr) increase in the expression of egr-1 that is followed (12-24 hr) by upregulation of angiogenic growth factors (e.g., VEGF, bFGF, PDGF). Surprisingly, this event is also associated with an enhanced production of angiostatin & endostatin that probably counteract the beneficial effect of angiogenic molecules. Thus, the initial injury to endothelial & epithelial cells in DU seems to be aggravated (& not initiated) by HCl & proteolytic enzymes. The resulting mucosal necrosis does not rapidly heal because of the imbalance of VEGF & angiostatin/endostatin, hence duodenal ulcers develop. The experimental ulcers Selye described morphologically are now characterized at the molecular & genome level, involving unexpected mediators like ET-1, egr-1 & angiogenesis-related molecules. Key Words:
endothelin-1, early growth response 1, angiogenesis, VEGF , endostatin , angiostatin, duodenal ulceration
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