Serum response factor promotes re-epithelialization and muscular structure restoration during gastric ulcer healing.
OBJECTIVE
Serum response factor (SRF) regulates transcription of immediate early genes and muscle genes. In this study, we examined the role of SRF in gastric ulcer healing and the mechanisms involved.


METHODS
Gastric ulcers were induced in rats by serosal application of acetic acid. Gastric specimens were obtained sequentially after ulcer induction for analyses of SRF messenger RNA (mRNA), protein expression, and for immunohistochemistry. We examined the role of SRF in ulcer healing by local injection of an SRF expression plasmid into ulcers (gene therapy). To elucidate the cellular mechanisms of the action of SRF, we examined the effect of SRF overexpression on actin dynamics, cell migration, and proliferation in rat gastric epithelial cell (RGM1) and smooth muscle cell (A7R5). To determine the clinical relevance, we examined SRF expression in human gastric ulcer specimens.


RESULTS
Gastric ulceration activated SRF expression in epithelial cells lining regenerating glands and in myofibroblasts and smooth muscle cells of granulation tissue. SRF up-regulation in human gastric ulcers was similar to that found in rat gastric ulcers. Gene therapy with SRF significantly accelerated experimental gastric ulcer healing and promoted re-epithelialization and muscle restoration. Overexpression of SRF in RGM1 and A7R5 cells accelerates migration and proliferation of these cells by promoting actin polymerization and activation of immediately early genes.


CONCLUSIONS
Activation of SRF is an important component of ulcer healing. SRF promotes migration and proliferation of gastric epithelial and smooth muscle cells, which are essential for re-epithelialization and restoration of muscular structures.
Chai
Jianyuan
J
Department of Medicine/Gastroenterology, VA Medical Center, 5901 East Seventh Street, Long Beach, CA 90822, USA.
Baatar
Dolgor
D
Tarnawski
Andrzej
A
D000818:Animals; D002455:Cell Division; D002465:Cell Movement; D018076:DNA, Complementary / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics; D051766:Early Growth Response Protein 1; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D015870:Gene Expression; D015316:Genetic Therapy; D017874:Immediate-Early Proteins / Q000235:genetics; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology*; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D026362:Serum Response Factor / Q000235:genetics* / Q000378:metabolism; D013276:Stomach Ulcer / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D022502:Stress Fibers / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D014945:Wound Healing / Q000502:physiology*
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D026362:Serum Response Factor; D014157:Transcription Factors