Genetic Evidence for a Protective Role of Heat Shock Factor 1 against Irritant-Induced Gastric Lesions
Genetic Evidence for a Protective Role of Heat Shock Factor 1 against Irritant-Induced Gastric Lesions
复制标题
DOI：
10.1124/mol.106.033282
复制
发表时间：
2007-04
影响因子：
3.6
通讯作者：
Ken-ichiro Tanaka;S. Tsutsumi;Yasuhiro Arai;Tatsuya Hoshino;Keitarou Suzuki;E. Takaki;Takaaki Ito;K. Takeuchi;A. Nakai;T. Mizushima
中科院分区：
文献类型：
--
作者：
Ken-ichiro Tanaka;S. Tsutsumi;Yasuhiro Arai;Tatsuya Hoshino;Keitarou Suzuki;E. Takaki;Takaaki Ito;K. Takeuchi;A. Nakai;T. Mizushima
胃病变是由于侵袭性和防御性因素之间的不平衡造成的。间接证据表明，各种侵袭因子诱导的热休克蛋白（HSPs）提供了主要的保护机制。在这项研究中，我们比较了野生型小鼠和缺乏热休克因子1 （HSF1）的小鼠的胃溃疡发生反应，HSF1是热休克基因的转录因子。hsf1缺失小鼠的胃损伤严重程度加重。免疫印迹、实时逆转录聚合酶链反应、免疫组织化学分析和末端脱氧核苷酸转移酶dUTP镍端标记实验显示，乙醇给药可上调胃黏膜热休克蛋白，特别是HSP70，且以hsf1依赖的方式上调，hsf1缺失小鼠胃黏膜的凋亡细胞多于野生型小鼠。相比之下，控制胃溃疡发生反应的其他参数，包括胃酸分泌、胃黏膜血流量和前列腺素E2水平，不受hsf1基因缺失的显著影响。Geranylgeranylacetone （GGA）是一种临床使用的抗溃疡药物，具有热休克因子诱导活性，在野生型小鼠中抑制乙醇诱导的胃损伤，但在热休克因子1 （HSF1）缺失的小鼠中没有作用。结果提示，hsf1缺失小鼠刺激性胃损伤的加重是由于其无法上调HSPs，导致细胞凋亡。这也表明GGA的热休克蛋白诱导活性有助于药物的抗溃疡活性。本研究提供了直接的遗传证据，证明热休克蛋白在其hsf1依赖性上调后，可以保护胃免受刺激物引起的病变。
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 E2 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.