HEAT SHOCK PROTEIN GENE EXPRESSION IN RESPONSE TO STRESS AND AGING

响应压力和衰老的热休克蛋白基因表达

• 批准号: 3745538
• 负责人: N J HOLBROOK
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3745538
• 关键词: adrenal glands; age difference; aging; aorta; biological signal transduction; blood vessel transplantation; gene expression; genetic promoter element; genetic transcription; laboratory rat; neuroendocrine system; restraint; stress; stress proteins; stressor; transcription factor; western blottings

Heat shock proteins (HSPs) are induced in response to a variety of cellular stresses, and appear to be critical for maintaining cellular homeostasis. Previously, we demonstrated that restraint or immobilization stress elicits the induction of HSP7O expression selectively in the adrenal gland and vasculature of intact rats. In both tissues this stress-induced HSP7O expression was found to be linked to the activation of the neuroendocrine stress response axes and to be attenuated with age. The adrenal response was found to be dependent on the hypothalamic-pituitary-adrenal axis and require adrenocorticotropic hormone (ACTH) while the vascular response appeared to be under alpha adrenergic control. Recent studies have focused on the molecular events controlling this response to restraint and the cause for its age-related decline. In the adrenal model we have shown that HSP7O induction is mediated by the heat shock transcription factor HSF1 and have shown that in Wistar rats HSF1 is activated to a DNA binding state by ACTH. Although properties of HSF1 and its activation in response to heat stress have been well studied in cultured cells, little information is available regarding the regulation of its activity in vivo. We have noted a number of differences in the properties of HSF1 in our in vivo model compared to that observed in heat stressed cells in vitro. These include the subcellular localization of HSF1 (which is mostly nuclear in the adrenal gland) and the differential mobility and DNA binding properties of the transcription factor in different rat strains. Despite differences in the nature of DNA binding HSF complexes in two different rat strains, the level DNA binding activity declines with age in both. In vascular tissue we have provided new evidence that in addition to adrenergic hormones, other agents capable of elevating blood pressure likewise induce HSP7O expression in the aorta. This suggests that mechanical stress associated with changes in blood pressure elicit the response. Our findings indicate that the activation of the heat shock response in vivo involves greater complexity than is observed in cultured cells in response to heat stress and suggest a broader role for HSPs in the physiologic response to stress than previously appreciated.

热休克蛋白（HSPs）是在对多种应激反应的反应中诱导产生的。 细胞的压力，似乎是至关重要的维持 细胞内稳态此前，我们证明了克制或 束缚应激诱导HSP 7 O表达 选择性地存在于完整大鼠的肾上腺和脉管系统中。在 这两种组织中，这种应激诱导的HSP 7 O表达被发现是 与神经内分泌应激反应轴的激活有关 并随着年龄的增长而衰减。肾上腺反应被发现是 依赖于下丘脑-垂体-肾上腺轴， 促肾上腺皮质激素（ACTH），而血管反应 似乎是受α肾上腺素能控制的最近的研究 专注于控制这种反应的分子事件， 抑制和其与年龄相关的下降的原因。肾上腺 我们的模型表明，热休克蛋白70的诱导是由热介导的， 休克转录因子HSF 1，并已显示在Wistar大鼠中 HSF 1被ACTH激活至DNA结合状态。虽然 HSF 1的特性及其在热应激反应中的活化 已经在培养细胞中进行了很好的研究， 关于其在体内的活性的调节。我们有 在我们的研究中， 与在热应激细胞中观察到的相比， 体外这些包括HSF 1的亚细胞定位（其是 大多数是肾上腺中的细胞核）和差异迁移率 和DNA结合特性的转录因子在不同的 老鼠品系。尽管DNA结合HSF的性质不同， 复合物在两个不同的大鼠品系，水平DNA结合 两者的活性都随着年龄的增长而下降。在血管组织中， 提供了新的证据，除了肾上腺素能激素， 能够升高血压的其它药剂同样诱导 主动脉HSP 70表达。这表明机械应力 与血压变化相关的反应。我们 研究结果表明，热休克反应的激活， 在体内涉及比在培养细胞中观察到的更大的复杂性 并提示热休克蛋白在热应激反应中的广泛作用， 对压力的生理反应比以前认识到的要大。