Ferrochelatase regulates retinal neovascularization.
Ferrochelatase regulates retinal neovascularization.
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DOI：
10.1096/fj.202000964r
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Corson TW
中科院分区：
文献类型：
--
作者：
Pran Babu SPS;White D;Corson TW
亚铁螯合酶（FECH）是血红素生物合成的末端酶。我们以前表明，FECH是所需的内皮细胞生长在体外和脉络膜新生血管在体内。但FECH尚未在视网膜新生血管中进行探索，而视网膜新生血管是增殖性糖尿病视网膜病变和早产儿视网膜病变等疾病的基础。在这里，我们研究了使用遗传和化学方法在氧诱导的视网膜病变（OIR）小鼠模型中抑制FECH。在OIR小鼠中，FECH表达上调并与新生血管簇共定位。部分功能丧失的Fechm 1 Pas突变小鼠在OIR中表现出视网膜新生血管和内皮细胞增殖的减少。玻璃体内注射FECH抑制剂N-甲基原卟啉也有类似的效果。灰黄霉素是一种抗真菌药物，抑制FECH作为脱靶效应。引人注目的是，玻璃体内灰黄霉素减少病理性簇形成和血管闭塞的地区相比，车辆，这表明作为FECH靶向治疗的潜力。眼毒性研究表明，玻璃体内注射灰黄霉素在成年小鼠不破坏视网膜血管，功能，或形态。总之，Fech的突变和化学抑制减少视网膜新生血管形成并促进生理性血管生成，表明FECH抑制后对血管修复的双重作用，而无眼毒性。这些发现表明，FECH抑制剂可用于治疗视网膜新生血管。
Ferrochelatase (FECH) is the terminal enzyme in heme biosynthesis. We previously showed that FECH is required for endothelial cell growth in vitro and choroidal neovascularization in vivo. But FECH has not been explored in retinal neovascularization, which underlies diseases like proliferative diabetic retinopathy and retinopathy of prematurity. Here, we investigated the inhibition of FECH using genetic and chemical approaches in the oxygen-induced retinopathy (OIR) mouse model. In OIR mice, FECH expression is upregulated and co-localized with neovascular tufts. Partial loss-of-function Fechm1Pas mutant mice showed reduced retinal neovascularization and endothelial cell proliferation in OIR. An intravitreal injection of the FECH inhibitor N-methyl protoporphyrin had similar effects. Griseofulvin is an anti-fungal drug that inhibits FECH as an off-target effect. Strikingly, intravitreal griseofulvin decreased both pathological tuft formation and areas of vasoobliteration compared to vehicle, suggesting potential as a FECH-targeting therapy. Ocular toxicity studies revealed that intravitreal injection of griseofulvin in adult mice does not disrupt retinal vasculature, function, or morphology. In sum, mutation and chemical inhibition of Fech reduces retinal neovascularization and promotes physiological angiogenesis, suggesting a dual effect on vascular repair upon FECH inhibition, without ocular toxicity. These findings suggest that FECH inhibitors could be repurposed to treat retinal neovascularization.
影响因子：
3.7
作者：
DeNiro M;Al-Mohanna FH;Al-Mohanna FA
通讯作者：
Al-Mohanna FA