Heat Shock Protein 70 (HSP70) Is Critical for the Photoreceptor Stress Response after Retinal Detachment via Modulating Anti-Apoptotic Akt Kinase
Heat Shock Protein 70 (HSP70) Is Critical for the Photoreceptor Stress Response after Retinal Detachment via Modulating Anti-Apoptotic Akt Kinase
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DOI：
10.1016/j.ajpath.2010.11.072
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发表时间：
2011-03-01
影响因子：
6
通讯作者：
Miller, Joan W.
中科院分区：
文献类型：
--
作者：
Kayama, Maki;Nakazawa, Toru;Miller, Joan W.
光感受器细胞凋亡是许多眼科疾病导致视力丧失的主要原因。在阐明这一过程中涉及的分子途径方面已经取得了重大进展，但对对抗这些凋亡途径的蛋白质知之甚少。热休克蛋白(HSPs)是一种分子辅助蛋白(伴侣蛋白)，它通过阻止蛋白质聚集和促进功能失调的蛋白质的重折叠而发挥作用，对所有生物的生存至关重要。在这里，我们研究了HSP70在小鼠和大鼠实验性视网膜脱离(RD)后光感受器存活中的作用。我们发现，在RD后，HSP70表达上调，并与磷酸化Akt相关，从而阻止其去磷酸化和进一步激活细胞死亡途径。应用抑制HSP70和Akt磷酸化的槲皮素显著增加光感受器的凋亡。同样，在携带HSP70编码基因亚形态突变的小鼠中，RD诱导的光感受器凋亡也得到了增强。另一方面，香叶基香叶内酮通过延长ALA通路的激活，显著减少RD后光感受器细胞的凋亡，增加HSP70表达。因此，HSP70可能是提高视网膜脱离后光感受器细胞存活的一个有利的潜在靶点。(Am J Pathol2011,178：1080-1091；doi：10.1016/j.ajpath.2010.11.072)
Photoreceptor apoptosis is a major cause of vision loss in many ocular diseases. Significant progress has been made to elucidate the molecular pathways involved in this process, yet little is known about proteins counteracting these apoptotic pathways. It is established that heat shock proteins (HSPs) function as molecular helper proteins (chaperones) by preventing protein aggregation and facilitating refolding of dysfunctional proteins, critical to the survival of all organisms. Here, we investigated the role of HSP70 on photoreceptor survival after experimental retinal detachment (RD) in mice and rats. We found that HSP70 was up-regulated after RD and associated with phosphorylated Akt, thereby preventing its dephosphorylation and further activation of cell death pathways. Administration of quercetin, which inhibits HSP70 and suppresses Akt phosphorylation significantly increased photoreceptor apoptosis. Similarly, RD-induced photoreceptor apoptosis was augmented in mice carrying hypomorphic mutations of the genes encoding HSP70. On the other hand, administration of geranylgeranylacetone, which induces an increase in HSP70 significantly decreased photoreceptor apoptosis after RD through prolonged activation of Ala pathway. Thus, HSP70 may be a favorable potential target to increase photoreceptor cell survival after RD. (Am J Pathol 2011, 178:1080-1091; DOI: 10.1016/j.ajpath.2010.11.072)