Heat-shock factor-1, steroid hormones, and regulation of heat-shock protein expression in the heart
Heat-shock factor-1, steroid hormones, and regulation of heat-shock protein expression in the heart
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DOI：
10.1152/ajpheart.2001.280.1.h455
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发表时间：
2001-01-01
影响因子：
4.8
通讯作者：
Sun, LM
中科院分区：
文献类型：
--
作者：
Knowlton, AA;Sun, LM
热休克蛋白 (HSP) 是一个重要的内源性保护蛋白家族。 HSP 的过度表达可预防心脏损伤。此前，我们观察到地塞米松激活热休克因子-1 (HSF-1) 并诱导成人心肌细胞中 HSP72 增加 60%。地塞米松产生这种作用的机制尚不清楚。由于已知 HSP90 与细胞内激素受体结合，因此我们推测 HSP90、受体和 HSF 之间的相互作用是激素激活 HSF-1 的重要因素。我们假设 HSP90 与其结合的各种受体/酶之间存在平衡，并且某些激素水平的改变将改变 HSP90 的细胞内分布并激活 HSF-1。我们报道，在成人心肌细胞中，HSF-1 与 HSP90 共免疫沉淀。用 17 β-雌二醇或黄体酮治疗后，HSP90 在心肌细胞中重新分布。雌激素和孕激素激活成年男性分离心肌细胞中的 HSF-1，随后 HSP72 蛋白增加。睾酮对 HSP 水平没有影响；然而，在心肌细胞中没有发现雄激素受体；因此，预计睾酮不会影响 HSP90 与 HSF 的结合。格尔德霉素可灭活 HSP90 并阻止其与受体结合，激活 HSF-1 并刺激 HSP72 合成。由于 HSP90 和 HSF-1 相互作用的变化，类固醇激素对 HSF-1 的激活代表了调节 HSP 表达的新途径。这些发现可以解释心血管疾病的一些性别差异。
Heat-shock proteins (HSPs) are an important family of endogenous, protective proteins. Overexpression of HSPs is protective against cardiac injury. Previously, we observed that dexamethasone activated heat-shock factor-1 (HSF-1) and induced a 60% increase in HSP72 in adult cardiac myocytes. The mechanism responsible for this effect of dexamethasone is unknown. Because HSP90 is known to bind the intracellular hormone receptors, we postulated that the interaction between HSP90, the receptors, and HSF was an important element in activation of HSF-1 by hormones. We hypothesized that there is an equilibrium between HSP90 and the various receptors/enzymes that it binds and that alteration in levels of certain hormones will alter the intracellular distribution of HSP90 and activate HSF-1. We report that, in adult cardiac myocytes, HSF-1 coimmunoprecipitates with HSP90. HSP90 redistributes in cardiac myocytes after treatment with 17 beta -estradiol or progesterone. Estrogen and progesterone activate HSF-1 in adult male isolated cardiac myocytes, and this is followed by an increase in HSP72 protein. Testosterone had no effect on HSP levels; however, no androgen receptor was found in cardiac myocytes; therefore, testosterone would not be expected to effect binding of HSP90 to HSF. Geldanamycin, which inactivates HSP90 and prevents it from binding to receptors, activates HSF-1 and stimulates HSP72 synthesis. Activation of HSF-1 by steroid hormones, resulting from a change in the interaction of HSP90 and HSF-1, represents a novel pathway for regulating expression of HSPs. These findings may explain some of the gender differences in cardiovascular disease.