24(S)-Hydroxycholesterol protects the ex vivo rat retina from injury by elevated hydrostatic pressure.
24(S)-Hydroxycholesterol protects the ex vivo rat retina from injury by elevated hydrostatic pressure.
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24（S） - 羟基胆固醇可通过静水压力升高来保护离体大鼠视网膜免受损伤。
DOI：
10.1038/srep33886
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发表时间：
2016-09-22
影响因子：
4.6
通讯作者：
Izumi Y
中科院分区：
文献类型：
--
作者：
Ishikawa M;Yoshitomi T;Zorumski CF;Izumi Y
在中枢神经系统中，24（S）-羟基胆固醇（24（S）-HC）是由cyp 46 a1基因编码的胆固醇24-羟化酶（CYP 46 A1）从胆固醇合成的氧化固醇。在本研究中，使用大鼠离体青光眼模型，我们发现视网膜24（S）-HC的合成是由压力升高促进。此外，我们发现24（S）-HC对压力介导的视网膜变性具有神经保护作用。实时定量RT-PCR、ELISA和免疫组化显示，压力升高促进了CYP 46 A1和CYP 46 A1的表达。免疫组化结果显示，CYP 46 A1主要在视网膜神经节细胞（RGC）表达增强。LC-MS/MS显示24（S）-HC水平以压力依赖性方式增加。外源性给予1 μM 24（S）-HC可减轻75 mmHg高压诱导的轴突损伤和RGC凋亡。相比之下，伏立康唑，CYP 46 A1抑制剂，是严重的毒性，即使在常压。在常压条件下，需要30 μM 24（S）-HC才能预防伏立康唑介导的视网膜损伤。综上所述，我们的研究结果表明，24（S）-HC是由高压促进，并发挥神经保护作用，在昏迷的条件下，而伏立康唑，抗真菌药物，是视黄毒性。24（S）-HC和相关化合物可能作为潜在的治疗靶点，用于保护青光眼眼免受压力诱导的损伤。
In the central nervous system, 24(S)-hydroxycholesterol (24(S)-HC) is an oxysterol synthesized from cholesterol by cholesterol 24-hydroxylase (CYP46A1) encoded by the cyp46a1 gene. In the present study using a rat ex vivo glaucoma model, we found that retinal 24(S)-HC synthesis is facilitated by pressure elevation. Moreover, we found that 24(S)-HC is neuroprotective against pressure mediated retinal degeneration. Quantitative real-time RT-PCR, ELISA, and immunohistochemistry revealed that elevated pressure facilitated the expression of cyp46a1 and CYP46A1. Immunohistochemically, the enhanced expression of CYP46A1 was mainly observed in retinal ganglion cells (RGC). LC-MS/MS revealed that 24(S)-HC levels increased in a pressure-dependent manner. Axonal injury and apoptotic RGC death induced by 75 mmHg high pressure was ameliorated by exogenously administered 1 μM 24(S)-HC. In contrast, voriconazole, a CYP46A1 inhibitor, was severely toxic even at normobaric pressure. Under normobaric conditions, 30 μM 24(S)-HC was required to prevent the voriconazole-mediated retinal damage. Taken together, our findings indicate that 24(S)-HC is facilitated by elevated pressure and plays a neuroprotective role under glaucomatous conditions, while voriconazole, an antifungal drug, is retinotoxic. 24(S)-HC and related compounds may serve as potential therapeutic targets for protecting glaucomatous eyes from pressure-induced injuries.
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影响因子：
--
作者：
Gao, H;Pennesi, ME;Holz, ER
通讯作者：
Holz, ER
影响因子：
15.9
作者：
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影响因子：
4.8
作者：
Bjorkhem, I;Lutjohann, D;Wennmalm, A
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Wennmalm, A
影响因子：
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作者：
Ishikawa, Makoto;Yoshitomi, Takeshi;Izumi, Yukitoshi
通讯作者：
Izumi, Yukitoshi
影响因子：
3
作者：
IZUMI, Y;BENZ, AM;OLNEY, JW
通讯作者：
OLNEY, JW