Department of Neurology, University of California at Davis, Sacramento, CA, 95817, USA.
Transl Stroke Res. 2013 Dec;4(6):685-92. doi: 10.1007/s12975-013-0271-4. Epub 2013 Aug 3.
Heat shock proteins (Hsps) are induced by heat shock via heat shock factor 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. Overexpression of Hsp70 via transgenes and viruses or systemic administration of Hsp70 fusion proteins that allow it to cross the blood brain barrier protects the 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 the brain, protein kinase D phosphorylates Hsp27 following ischemia which then binds apoptosis signal-regulating kinase 1 to prevent MKK4/7, c-Jun NH(2)-terminal kinase, and 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.
热休克蛋白（Hsps）通过热休克因子蛋白与启动子中热休克元件结合而被热休克诱导。在所有细胞类型中，脑缺血后，Hsp70 大量诱导以应对错误折叠的蛋白质，但主要在缺血半影区的神经元中诱导。通过转基因和病毒过表达 Hsp70 或全身给予允许其穿过血脑屏障的 Hsp70 融合蛋白，可以在大多数报道的研究中保护大脑免受缺血。Hsp27 可以存在为未磷酸化的大寡聚体，以防止错误折叠的蛋白质聚集并改善细胞存活。P-Hsp27 小寡聚体结合特定的蛋白质靶标以改善存活。在大脑中，缺血后蛋白激酶 D 使 Hsp27 磷酸化，然后与凋亡信号调节激酶 1 结合，以防止 MKK4/7、c-Jun NH(2)-末端激酶和 Jun 诱导的凋亡，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，胆绿素转化为胆红素，可作为抗氧化剂，两者都可能有助于 HO-1 在脑缺血和蛛网膜下腔出血中的报道保护作用。然而，亚铁离子可以与过氧化氢反应生成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，尚未在临床上进行测试。
