Sofalcone, a gastric mucosa protective agent, increases vascular endothelial growth factor via the Nrf2-heme-oxygenase-1 dependent pathway in gastric epithelial cells.
Sofalcone, 2'-carboxymethoxy-4,4-bis(3-methyl-2-butenyloxy)chalcone, is an anti-ulcer agent that is classified as a gastric mucosa protective agent. Recent studies indicate heat shock proteins such as HSP32, also known as heme-oxygenase-1(HO-1), play important roles in protecting gastrointestinal tissues from several stresses. We have previously reported that sofalcone increases the expression of HO-1 in adipocytes and pre-adipocytes, although the effect of sofalcone on HO-1 induction in gastrointestinal tissues is not clear. In the current study, we investigated the effects of sofalcone on the expression of HO-1 and its functional role in rat gastric epithelial (RGM-1) cells. We found that sofalcone increased HO-1 expression in RGM-1 cells in both time- and concentration-dependent manners. The HO-1 induction was associated with the nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in RGM-1 cells. We also observed that sofalcone increased vascular endothelial growth factor (VEGF) production in the culture medium. Treatment of RGM-1 cells with an HO-1 inhibitor (tin-protoporphyrin), or HO-1 siRNA inhibited sofalcone-induced VEGF production, suggesting that the effect of sofalcone on VEGF expression is mediated by the HO-1 pathway. These results suggest that the gastroprotective effects of sofalcone are partly exerted via Nrf2-HO-1 activation followed by VEGF production.
Shibuya
Akiko
A
Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Onda
Kenji
K
Kawahara
Hirofumi
H
Uchiyama
Yuka
Y
Nakayama
Hiroko
H
Omi
Takamasa
T
Nagaoka
Masayoshi
M
Matsui
Hirofumi
H
Hirano
Toshihiko
T
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D002460:Cell Line; D047188:Chalcones / Q000494:pharmacology*; D019610:Cytoprotection; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D000897:Anti-Ulcer Agents; D047188:Chalcones; D051267:NF-E2-Related Factor 2; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C035032:sofalcone; D051547:Heme Oxygenase-1