Effect of long-term chronic hyperhomocysteinemia on retinal structure and function in the cystathionine-β-synthase mutant mouse.
Effect of long-term chronic hyperhomocysteinemia on retinal structure and function in the cystathionine-β-synthase mutant mouse.
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DOI：
10.1016/j.exer.2021.108894
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发表时间：
2022-01
影响因子：
3.4
通讯作者：
Smith, Sylvia B.
中科院分区：
文献类型：
--
作者：
Xiao, Haiyan;Wang, Jing;Barwick, Shannon R.;Yoon, Yisang;Smith, Sylvia B.
兴奋性氨基酸同型半胱氨酸（Hcy）水平升高与人类视网膜疾病（包括青光眼和黄斑变性）有关。目前尚不清楚Hcy水平升高是否致病。高同型半胱氨酸血症（Hhcy）模型已被证明可用于解决这一问题，包括缺乏胱硫醚β-合酶（CBS）的小鼠。Cbs +/−小鼠的血浆和视网膜Hcy水平增加约两倍。先前对Cbs +/−小鼠在出生后前10个月的视觉功能和结构的研究显示，神经节细胞轻度丢失，但电生理学改变最小。目前尚不清楚是否延长，慢性暴露于中度高同型半胱氨酸升高将导致视功能丧失和视网膜病变。本研究通过对20个月的Cbs +/−和Cbs +/+（WT）小鼠的视网膜功能/结构进行全面分析来解决这一问题，包括IOP、SD-OCT、暗视和明视ERG、模式ERG（pERG）和视敏度。收获眼睛用于Brn3a（神经节细胞）、二氢乙锭（氧化应激）和GFAP（神经胶质增生）的组织学和免疫组织化学分析。分析显示年龄/品系组间IOP无差异。在20个月时，Cbs +/−和WT小鼠的视力测量值约为0.36 c/d;两组之间的对比敏感度在两个年龄段均无差异。同样，SD-OCT、暗视/明视ERG和pERG显示20个月Cbs +/−和WT小鼠之间无差异。组织学检查时，视网膜结构有轻微破坏。形态学分析显示视网膜各层无显著差异。免疫组织化学显示，20个月时，在Cbs +/−和WT小鼠中，每100 μ m视网膜长度约有5个RGC。虽然与年轻（4个月）小鼠相比，老年（20个月）小鼠的氧化应激和神经胶质增生更大，但20个月的Cbs +/−和WT小鼠之间的这些参数没有差异。我们的结论是，慢性，中度高同型半胱氨酸（至少由于缺乏的CBS）是不伴随着视网膜结构/功能的变化，显着不同的年龄匹配的野生型同窝仔。尽管有相当多的证据表明，严重的Hhcy是有毒的视网膜，中度Hhcy似乎耐受视网膜提示代偿性细胞存活机制。
Elevated levels of the excitatory amino acid homocysteine (Hcy) have been implicated in retinal diseases in humans including glaucoma and macular degeneration. It is not clear whether elevated Hcy levels are pathogenic. Models of hyperhomocysteinemia (Hhcy) have proven useful in addressing this including mice with deficiency in the enzyme cystathionine β-synthase (CBS). Cbs+/− mice have a ~two-fold increase in plasma and retinal Hcy levels. Previous studies of visual function and structure in Cbs+/− mice during the first 10 months of life revealed mild ganglion cell loss, but minimal electrophysiological alterations. It is not clear whether extended, chronic exposure to moderate Hhcy elevation will lead to visual function loss and retinal pathology. The present study addressed this by performing comprehensive analyses of retinal function/structure in 20 month Cbs+/− and Cbs+/+ (WT) mice including IOP, SD-OCT, scotopic and photopic ERG, pattern ERG (pERG), and visual acuity. Eyes were harvested for histology and immunohistochemical analysis of Brn3a (ganglion cells), dihydroethidium (oxidative stress) and GFAP (gliosis). The analyses revealed no difference in IOP between groups for age/strain. Visual acuity measured ~0.36c/d for mice at 20 months in Cbs+/− and WT mice; contrast sensitivity did not differ between groups at either age. Similarly SD-OCT, scotopic/photopic ERG and pERG revealed no differences between 20 month Cbs+/− and WT mice. There was minimal disruption in retinal structure when eyes were examined histologically. Morphometric analysis revealed no significant differences in retinal layers. Immunohistochemistry revealed ~5 RGCs/100μm retinal length in both Cbs+/− and WT mice at 20 months. While there was greater oxidative stress and gliosis in older (20 month) mice versus young (4 month) mice, there was no difference in these parameters between the 20 month Cbs+/− and WT mice. We conclude that chronic, moderate Hhcy (at least due to deficiency of Cbs) is not accompanied by retinal structural/functional changes that differ significantly from age-matched WT littermates. Despite considerable evidence that severe Hhcy is toxic to retina, moderate Hhcy appears tolerated by retina suggesting compensatory cellular survival mechanisms.
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影响因子：
3.4
作者：
Miura, Gen;Wang, Minhua H.;Ivers, Kevin M.;Frishman, Laura J.
通讯作者：
Frishman, Laura J.
影响因子：
4.4
作者：
Dun, Ying;Thangaraju, Muthusamy;Smith, Sylvia B.
通讯作者：
Smith, Sylvia B.
影响因子：
4.8
作者：
Lee, Hakjoo;Smith, Sylvia B.;Yoon, Yisang
通讯作者：
Yoon, Yisang
影响因子：
2.3
作者：
Lin, Zhongjing;Huang, Shouyue;Zhong, Yisheng
通讯作者：
Zhong, Yisheng
影响因子：
3.4
作者：
Moore, P;El-Sherbeny, A;Smith, SB
通讯作者：
Smith, SB