Heat shock proteins in the brain: role of Hsp70, Hsp 27, and HO-1 (Hsp32) and their therapeutic potential.
Heat shock proteins in the brain: role of Hsp70, Hsp 27, and HO-1 (Hsp32) and their therapeutic potential.
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DOI：
10.1007/s12975-013-0271-4
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发表时间：
2013-12
影响因子：
6.9
通讯作者：
Liu, Da-Zhi
中科院分区：
文献类型：
--
作者：
Sharp, Frank R.;Zhan, Xinhua;Liu, Da-Zhi
热休克蛋白是由热休克通过HSF蛋白与其启动子中的热休克元件结合而诱导的。热休克蛋白70是大量诱导的错误折叠的蛋白质脑缺血后，在所有类型的细胞，但主要是在缺血半暗带的神经元诱导。在大多数报道的研究中，通过转基因和病毒过表达Hsp 70或全身施用Hsp 70融合蛋白使其穿过血脑屏障保护脑免受缺血。热休克蛋白27可以作为非磷酸化的大寡聚体存在，防止错误折叠的蛋白质聚集并提高细胞存活。P-Hsp 27小寡聚体结合特异性蛋白质靶标以改善存活。在脑中，蛋白激酶D在缺血后磷酸化Hsp 27，然后结合ASK 1以防止MKK 4/7、JNK、Jun诱导的细胞凋亡并减少局灶性脑缺血后的梗死体积。血红素加氧酶-1（HO-1）将血红素代谢为一氧化碳、亚铁离子和胆绿素。CO激活cGMP以促进血管舒张，并且胆绿素转化为胆红素，胆红素可以用作抗氧化剂，这两者都可能有助于HO-1在脑缺血和蛛网膜下腔出血中的保护作用。然而，亚铁离子可与过氧化氢反应产生促氧化剂羟基自由基，这可能解释了HO-1在脑出血中的有害作用。热休克蛋白作为一类具有治疗脑血管疾病的巨大潜力，但尚未在临床上进行测试。
Heat shock proteins are induced by heat shock via HSF proteins binding to heat shock elements in their promoters. Hsp70 is massively induced in response to misfolded proteins following cerebral ischemia in all cell types, but is induced mainly in neurons in the ischemic penumbra. Over expression of Hsp70 via transgenes and viruses or systemic administration of Hsp70 fusion proteins that allow it to cross the blood brain barrier protect brain against ischemia in most reported studies. Hsp27 can exist as unphosphorylated large oligomers that prevent misfolded protein aggregates and improve cell survival. P-Hsp27 small oligomers bind specific protein targets to improve survival. In brain Protein Kinase D phosphorylates Hsp27 following ischemia which then binds ASK1 to prevent MKK4/7, JNK, Jun induced apoptosis and decrease infarct volumes following focal cerebral ischemia. Heme oxygenase-1 (HO-1) metabolizes heme to carbon monoxide, ferrous ion and biliverdin. CO activates cGMP to promote vasodilation, and biliverdin is converted to bilirubin which can serve as an anti-oxidant both of which may contribute to the reported protective role of HO-1 in cerebral ischemia and subarachnoid hemorrhage. However, ferrous ion can react with hydrogen peroxide to produce pro-oxidant hydroxyl radicals which may explain the harmful role of HO-1 in intracerebral hemorrhage. Heat shock proteins as a class have great potential as treatments for cerebrovascular disease and have yet to be tested in the clinic.
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