Genetic Evidence for a Protective Role of Heat Shock Factor 1 against Irritant-Induced Gastric Lesions

Abstract

Gastric lesions result from an imbalance between aggressive and defensive factors. Indirect lines of evidence suggest that heat shock proteins (HSPs) induced by various aggressive factors provide a major protective mechanism. In this study, we compared gastric ulcerogenic response in wild-type mice and in those lacking heat shock factor 1 (HSF1), a transcription factor for hsp genes. The severity of gastric lesions induced by ethanol or hydrochloric acid was worsened in HSF1-null mice. Immunoblotting, real-time reverse transcription-polymerase chain reaction, immunohistochemical analysis, and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay revealed that the ethanol administration up-regulated gastric mucosal HSPs, in particular HSP70, in an HSF1-dependent manner, and more apoptotic cells were observed in the gastric mucosa of HSF1-null mice than in wild-type mice. In contrast, other parameters governing the gastric ulcerogenic response, including gastric acid secretion, gastric mucosal blood flow, and prostaglandin E 2 levels, were not significantly affected by the absence of the hsf1 gene. Geranylgeranylacetone (GGA), a clinically used antiulcer drug with HSP-inducing activity, suppressed ethanol-induced gastric lesions in wild-type mice but not in heat shock factor 1 (HSF1)-null mice. The results suggest that the aggravation of irritant-induced gastric lesions in HSF1-null mice is due to their inability to up-regulate HSPs, leading to apoptosis. It is also suggested that the HSP-inducing activity of GGA contributes to the drug's antiulcer activity. This study provides direct genetic evidence that HSPs, after their HSF1-dependent up-regulation, confer gastric protection against the irritant-induced lesions.The balance between aggressive and defensive factors determines development of gastric lesions, with either a relative increase in aggressive insults or a relative decrease in protective factors, resulting in lesions. The gastric mucosa is challenged by a variety of both endogenous and exogenous irritants (aggressive factors), including ethanol, gastric acid, pepsin, reactive oxygen species, nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori. These irritants damage the mucosal cells, inducing cell death, which leads to the formation of gastric lesions (Holzer, 1998). To protect the gastric mucosa, a complex defense system, which includes the production of surface mucus and bicarbonate and the regulation of gastric mucosal blood flow (GMBF), has evolved. Prostaglandins (PGs), in particular PGE 2 , enhance these protective mechanisms and are therefore believed to comprise a major gastric mucosal defensive factor (Miller, 1983).Heat shock proteins (HSPs) have also attracted considerable attention as another major defensive factor. When cells are exposed to stressors, a number of so-called stress proteins are induced to confer protection against such stressors. HSPs

Genetic Evidence for a Protective Role for Heat Shock Factor 1 and Heat Shock Protein 70 against Colitis

“…A number of reports using HSF1-null mice and/or transgenic mice expressing HSP70 have shown that HSF1-dependent induction of HSP expression is protective against the development of various diseases, such as gastric ulcers, heart failure, pancreatitis, hypoxic/ischemic brain injury, and spinal and bulbar muscular atrophy (42)(43)(44)(45)(46). Because some HSPs have been reported to be overexpressed in the intestinal tissues of IBD patients (19,20,23) and in an animal model of IBD (21)(22)(23).…”

An acylic polyisoprenoid derivative, geranylgeranylacetone protects against visceral adiposity and insulin resistance in high-fat-fed mice

“…Although we observed that the effects of GGA correlated with HSP72 induction, we could not completely prove that GGA improves glucose metabolism only through the HSP72-JNK pathway. It is necessary to assess the impact of the HSP72-JNK pathway using HSP72-knockout mice and/or HSF1-knockout mice (48) to determine whether the beneficial effects of GGA are exerted mainly through HSP72.…”

Hsp70 Inhibits Aminoglycoside-Induced Hair Cell Death and is Necessary for the Protective Effect of Heat Shock

“…In addition, Hsf1 is required for normal development of the placenta, and female Hsf1 −/− mice are infertile (Xiao et al 1999;Christians et al 2000). Hsf1 −/− mice are more susceptible to lipopolysaccharide-induced mortality, cadmium-induced pulmonary damage, and hydrochloric acid-or ethanol-induced gastric lesions (Xiao et al 1999;Wirth et al 2004;Tanaka et al 2007). In the auditory system, Hsf1 −/− mice demonstrate increased susceptibility to noise trauma (Sugahara et al 2003;Fairfield et al 2005).…”