Why are some amyloidoses systemic? Does hepatic "chaperoning at a distance" prevent cardiac deposition in a transgenic model of human senile systemic (transthyretin) amyloidosis?
Why are some amyloidoses systemic? Does hepatic "chaperoning at a distance" prevent cardiac deposition in a transgenic model of human senile systemic (transthyretin) amyloidosis?
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DOI：
10.1096/fj.11-189571
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发表时间：
2012-06-01
期刊：
影响因子：
4.8
通讯作者：
Salomon, Daniel R.
中科院分区：
文献类型：
--
作者：
Buxbaum, Joel N.;Tagoe, Clement;Salomon, Daniel R.
在由突变型或野生型甲状腺素运载蛋白（TTR）引起的人类系统性淀粉样变性中，沉积发生在距离合成位点一定距离处。由肝细胞合成和分泌的TTR在血浆中循环，然后沉积在远离产生细胞的靶组织中，这种模式在转基因小鼠中重现，该小鼠具有多个人类野生型TTR基因拷贝。到2岁时，一半的转基因雄性显示类似于人类老年系统性淀粉样变性的心脏沉积。然而，早在3月龄时，当没有沉积物时，心脏基因转录与非转基因同窝仔不同，主要是在与炎症和免疫应答相关的大量基因的表达中。在24个月时，相对于没有TTR沉积的心脏，具有组织学证实的TTR沉积的心脏显示应激反应基因的表达、旺盛的线粒体基因转录以及与细胞凋亡相关的基因的表达增加。这些24个月大的TTR沉积心脏也显示出炎症基因的转录相对于年轻的转基因小鼠减少。在表达大量人类TTR 2年后，无心脏沉积的转基因小鼠的肝脏显示伴侣基因表达和激活的未折叠蛋白反应的证据，而心脏TTR沉积的动物的肝脏显示两者都没有，显示干扰素反应性炎症基因和编码抗氧化反应的基因的转录增加。随着时间的推移，在心脏沉积的动物中，似乎肝脏蛋白质稳定能力减弱，使心脏暴露于更大的错误折叠TTR负荷，随后发生细胞外沉积。因此，全身（心脏）TTR沉积可能是与年龄或长期暴露于错误折叠的TTR相关的肝脏远端陪伴能力降低的直接结果。Buxbaum，J. N.，塔戈角，加洛，G.，步行者，J.R.，Kurian，S.，Salomon，D. R.为什么有些淀粉样变性是系统性的？在人类老年系统性（甲状腺素运载蛋白）淀粉样变性转基因模型中，肝脏“远距离陪伴”是否能预防心脏沉积？FASEB J.26，2283-2293（2012）。www.fasebj.org
In the human systemic amyloidoses caused by mutant or wild-type transthyretin (TTR), deposition occurs at a distance from the site of synthesis. The TTR synthesized and secreted by the hepatocyte circulates in plasma, then deposits in target tissues far from the producing cell, a pattern reproduced in mice transgenic for multiple copies of the human wild-type TTR gene. By 2 yr of age, half of the transgenic males show cardiac deposition resembling human senile systemic amyloidosis. However, as early as 3 mo of age, when there are no deposits, cardiac gene transcription differs from that of nontransgenic littermates, primarily in the expression of a large number of genes associated with inflammation and the immune response. At 24 mo, the hearts with histologically proven TTR deposits show expression of stress response genes, exuberant mitochondrial gene transcription, and increased expression of genes associated with apoptosis, relative to the hearts without TTR deposition. These 24-mo-old hearts with TTR deposits also show a decrease in transcription of inflammatory genes relative to that in the younger transgenic mice. After 2 yr of expressing large amounts of human TTR, the livers of the transgenic mice without cardiac deposition display chaperone gene expression and evidence of an activated unfolded protein response, while the livers of animals with cardiac TTR deposition display neither, showing increased transcription of interferon-responsive inflammatory genes and those encoding an antioxidant response. With time, in animals with cardiac deposition, it appears that hepatic proteostatic capacity is diminished, exposing the heart to a greater load of misfolded TTR with subsequent extracellular deposition. Hence systemic (cardiac) TTR deposition may be the direct result of the diminution in the distant chaperoning capacity of the liver related to age or long-standing exposure to misfolded TTR, or both.-Buxbaum, J. N., Tagoe, C., Gallo, G., Walker, J. R., Kurian, S., Salomon, D. R. Why are some amyloidoses systemic? Does hepatic "chaperoning at a distance" prevent cardiac deposition in a transgenic model of human senile systemic (transthyretin) amyloidosis? FASEB J. 26, 2283-2293 (2012). www.fasebj.org