Age-related cataracts: homocysteine coupled endoplasmic reticulum stress and suppression of Nrf2-dependent antioxidant protection.
Age-related cataracts: homocysteine coupled endoplasmic reticulum stress and suppression of Nrf2-dependent antioxidant protection.
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DOI：
10.1016/j.cbi.2012.08.017
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发表时间：
2012-10-25
影响因子：
5.1
通讯作者：
Shinohara, Toshimichi
中科院分区：
文献类型：
--
作者：
Elanchezhian, Rajan;Palsamy, Periyasamy;Madson, Christian J.;Lynch, David W.;Shinohara, Toshimichi
探讨高水平的同型半胱氨酸（Hcy）是否通过抑制晶状体上皮细胞（LECs）中核因子-红细胞2相关因子2 （Nrf2）依赖的抗氧化保护诱导内质网（ER）应激。内皮细胞暴露于100 μM Hcy（不含FCS）和5 mM Hcy（含10% FCS）均可急性诱导内质网应激。暴露于Hcy后，24 h内P-PERK、P-eIF2α、XBP1、Nrf2和Keap1均发生显著变化。暴露于Hcy后，活性氧（ROS）的产生增加。Nrf2样下游酶过氧化氢酶和谷胱甘肽还原酶显著降低。这些结果表明，hcy诱导的内质网应激抑制了nrf2依赖的抗氧化保护，同时产生ROS，导致lec进一步氧化和死亡。Nrf2的丢失主要是由于蛋白体降解和细胞质Ca++水平升高激活m-calpain。半胱天冬酶也在Nrf2的降解中发挥作用。我们的研究结果表明，高水平的Hcy诱导内质网应激，慢性UPR，改变UPR特异性蛋白的水平，增加ROS的产生，降解Nrf2并阻断lec中Nrf2依赖的抗氧化防御保护。因此，ROS的上调可能超过了内皮细胞中Nrf2依赖的抗氧化防御保护，导致晶状体高度氧化，从而导致arc。
To determine whether high levels of homocysteine (Hcy) induce endoplasmic reticulum (ER) stress with suppression of the nuclear factor-erythroid-2-related factor 2 (Nrf2)-dependent antioxidant protection in lens epithelial cells (LECs). ER stress was acutely induced by exposure of LECs to 100 μM Hcy without FCS and also by exposure to 5 mM Hcy with 10% FCS. After exposure to Hcy, significant changes were found in P-PERK, P-eIF2α, XBP1, Nrf2, and Keap1 within 24 h. The production of reactive oxygen species (ROS) was increased after Hcy exposure. The downstream enzymes of Nrf2 like, catalase, and glutathione reductase, were significantly decreased. These results suggested that the Hcy-induced ER stress suppressed the Nrf2-dependent antioxidant protection and simultaneously generated ROS which resulted in further oxidation and death of LECs. The loss of Nrf2 is mainly due to proteosomal degradation and m-calpain activation by the increased levels of cytoplasmic Ca++. The caspases also play a role in the degradation of Nrf2. Our findings demonstrated that high levels of Hcy induce ER stress, chronic UPR, alter the levels of UPR specific proteins, increase the production of ROS, degrade Nrf2 and block the Nrf2-dependent antioxidant defense protection in LECs. Thus, the upregulation of ROS might exceed the Nrf2 dependent antioxidant defense protection in the LECs and result in the highly oxidized lenses and resulted in ARCs.
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影响因子：
3.4
作者：
Ikesugi, Kengo;Yamamoto, Ryoko;Shinohara, Toshimichi
通讯作者：
Shinohara, Toshimichi
影响因子：
3.4
作者：
HARDING, JJ
通讯作者：
HARDING, JJ
DOI：
10.1161/01.atv.0000023899.93940.7c
发表时间：
2002-08-01
影响因子：
8.7
作者：
Majors, AK;Sengupta, S;Jacobsen, DW
通讯作者：
Jacobsen, DW
影响因子：
2
作者：
Ikesugi, Kengo;Mulhern, Michael L.;Shinohara, Toshimichi
通讯作者：
Shinohara, Toshimichi
影响因子：
3.4
作者：
Nakajima, E.;Walkup, R. D.;Azuma, M.
通讯作者：
Azuma, M.