Apoptosis a programmed cell death, is an essential mechanism of eliminating damaged or aged cells and thus to maintain tissue integrity. There are two central pathways that lead to apoptosis: a) the positive induction by ligands (death factors) binding to plasma membrane receptors (death factor receptors) and b) negative induction by the loss of suppressor activity. The common execution mechanisms of apoptosis consist of the activation of cytosolic aspartate-specific proteases (ICE-proteases) termed caspases, which can be activated via various intracellular pathways. In the stomach, mucosal surface epithelial cells are constantly exfoliating to the gastric lumen and completely replaced within 3-5 days under physiological conditions. Apoptosis has been reported to take place in all regions of the stomach with apoptotic cells occurring predominantly in the superficial parts of the gastric glands, at a rate of 2-3% for all cells. Following mucosal injury (e.g. ulcer development), apoptosis rapidly increases and remains elevated for 2-3 months. In a 3-month old ulcer scar, the apoptosis rate of mucous, parietal, chief and endocrine cells was found to be similar to that of normal gastric mucosa. Helicobacter pylori (H. pylori) infection induces apoptosis in the gastric mucosa and this action appears to be independent of VacA cytotoxin of H. pylori strains. Nonsteroidal anti-inflammatory drugs (NSAIDs), especially cyclooxygenase-2 (COX-2) inhibitors are potent inductors of gastric epithelial cell apoptosis. However, they can abrogate apoptosis or proliferation effects induced by H. pylori. Many details of the exact intracellular and molecular mechanisms regulating apoptosis in gastric mucosa remain to be elucidated.

Impairment of angiogenesis - new capillary blood vessel formation from pre-existing vessels, is frequent in aging tissues and cells. Reduced angiogenesis in aging individuals is associated with increased incidence of myocardial infarctions and other cardiovascular diseases. Therefore there is a need to develop novel strategies to enhance angiogenesis in aging individuals. Our previous study demonstrated aging-related impairment of angiogenesis in aging (vs. young) rat myocardial microvascular endothelial cells (MMEC), and identified reduced activation of the vascular endothelial growth factor (VEGF, the most potent stimulator of angiogenesis) gene as the main underlying mechanism. In the present study we examined the possibility of increasing angiogenesis and activating VEGF gene expression in aging MMECs using a chemical activator of the metabolic sensor - AMP activated protein kinase (AMPK). We hypothesized that activation of VEGF gene in aging MMECs by AMPK would stimulate angiogenesis and reverse the impairment in angiogenesis seen in these cells. We used MMECs isolated from aging (24 months old) Fisher F-344 rats and treated them with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), a specific pharmacological stimulator of AMPK. We examined: 1) in vitro angiogenesis; and 2) the expression of phosphorylated AMPK, VEGF, and P-MAPK/Erk1/2. Treatment of aging MMECs with AICAR increased in vitro angiogenesis and VEGF mRNA expression by 2.1-fold and 3.7-fold, respectively. Furthermore, AICAR treatment resulted in phosphorylation of MAPK/Erk1/2. This study demonstrated the successful use AICAR to reverse aging-related impairment of angiogenesis in aging MMECs by enhancing VEGF gene expression and also identified phosphorylation of MAPK/Erk1/2 as a likely mechanism of these changes.

Serum response factor (SRF) is a transcription factor, which binds to a serum response element (SRE) associated with a variety of genes including immediate early genes such as c-fos, fosB, junB, egr-1 and -2, neuronal genes such as nurr1 and nur77 and muscle genes such as actins and myosins. By regulating expression of these genes, SRF controls cell growth and differentiation, neuronal transmission as well as muscle development and function. SRF can be activated by a variety of agents, including serum, lysophosphatidic acid (LPA), lipopolysaccharide (LPS), 12-O-tetradecanoylphorbol-13-acetate (TPA), cytokines, tumor necrosis factor-alpha (TNFalpha), agents that increase intracellular Ca2+, T-cell virus1 activator protein, hepatitis B virus activator proteins pX, activated oncogenes and protooncogenes as well as extracellular stimuli such as antioxidant and UV light. SRF itself is regulated by both cellular signal transduction pathways and interaction with other transcription factors e.g. Sp1, ATF6 and myogenic regulatory factors. Its biological function is best elucidated for myocardium. Specific cardiac SRF transgenesis demonstrated that overexpression of SRF caused hypertrophic cardiomyopathy in mouse and the mouse died of heart failure within 6 months after birth. Other transgenic data suggested that sufficient SRF was needed for embryogenesis and early development. Since SRF is important regulator of numerous genes involved in cell growth and differentiation, including muscle and neural components, SRF may also play a crucial role in tissue injury and ulcer healing, e.g. healing of gastrointestinal ulcers.

Apoptosis a programmed cell death, is an essential mechanism of eliminating damaged or aged cells and thus to maintain tissue integrity. There are two central pathways that lead to apoptosis: a) the positive induction by ligands (death factors) binding to plasma membrane receptors (death factor receptors) and b) negative induction by the loss of suppressor activity. The common execution mechanisms of apoptosis consist of the activation of cytosolic aspartate-specific proteases (ICE-proteases) termed caspases, which can be activated via various intracellular pathways. In the stomach, mucosal surface epithelial cells are constantly exfoliating to the gastric lumen and completely replaced within 3-5 days under physiological conditions. Apoptosis has been reported to take place in all regions of the stomach with apoptotic cells occurring predominantly in the superficial parts of the gastric glands, at a rate of 2-3% for all cells. Following mucosal injury (e.g. ulcer development), apoptosis rapidly increases and remains elevated for 2-3 months. In a 3-month old ulcer scar, the apoptosis rate of mucous, parietal, chief and endocrine cells was found to be similar to that of normal gastric mucosa. Helicobacter pylori (H. pylori) infection induces apoptosis in the gastric mucosa and this action appears to be independent of VacA cytotoxin of H. pylori strains. Nonsteroidal anti-inflammatory drugs (NSAIDs), especially cyclooxygenase-2 (COX-2) inhibitors are potent inductors of gastric epithelial cell apoptosis. However, they can abrogate apoptosis or proliferation effects induced by H. pylori. Many details of the exact intracellular and molecular mechanisms regulating apoptosis in gastric mucosa remain to be elucidated.

Serum response factor (SRF) is a transcription factor that is involved in cell proliferation, muscle and neuron development and maintenance. Its expression in gastric mucosa remains unknown. In this study we demonstrated that SRF is expressed in normal rat gastric tissue as two isoforms and localized mainly to smooth muscle cells of muscularis mucosae and its extensions into the lamina propria, to muscularis propria, and musculature of the vascular system. To a lesser extent, SRF is also expressed in the gastric epithelium of the mucosal neck area (proliferative zone) and in the endothelial cells of microvessels. These data suggest that the main role of SRF in normal gastric tissue is to maintain muscular support and contraction and possibly epithelial regeneration.