Fig. 7: Pharmacological inhibition of ATF4 rescues mouse models of glaucoma.
From: ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load
a C57 mice were injected with vehicle (n = 4) and Dex (n = 4) weekly via periocular conjunctival fornix injections. After 2 weeks, left eyes received 5 µl of 2 mM ISRIB topical eye drops while the contralateral right eyes received vehicle eye drops (DMSO) twice daily. One-week ISRIB treatment significantly lowered IOPs in Dex-injected left eyes compared to the contralateral right eyes (n = 4 biologically independent samples; data are presented as mean ± SEM, one-way ANOVA, Tukey’s multiple comparison test, **P < 0.01). b Western blot (Supplementary Fig. 21) and densitometric analysis b of mouse anterior segment lysates injected with vehicle or Dex for 2 weeks and treated with 5 µl of 2 mM ISRIB topical eye drops or DMSO control. ISRIB treatment prevented Dex-induced FN and ER stress markers (n = 3 biologically independent samples; data are presented as mean ± SEM, one-way ANOVA, **P < 0.01, ***P < 0.001, ****P < 0.0001). c The ocular hypertensive Tg.MYOCY437H mice received ISRIB eye drops in left eyes whereas the contralateral right eyes received vehicle (DMSO) eye drops twice daily. IOPs were recorded after one-week treatment (n = 5 biologically independent samples; data are presented as mean ± SEM, two-tailed paired t-test). d C57 mice were treated with Dex for 3 weeks via periocular route. IOPs were measured after 3 weeks. After ocular hypertension was confirmed, Ad5.ATF4ΔRK (2 × 107 pfu/eye) was injected intravitreally in the left eyes while the contralateral right eyes were injected with Ad5.Empty. Both eyes were treated with Dex for another week and IOPs were measured every week. Ad5.ATF4ΔRK reduced elevated IOP compared to contralateral eyes injected with Ad5. empty (n = 4 biologically independent samples; data are presented as mean ± SEM, two-tailed paired t-test). e–h Western blot e and its densitometric analyses f–h of mouse anterior segment lysates show that ATF4ΔRK prevented Dex-induced fibronectin and CHOP. n = 3 biologically independent samples; data are presented as mean ± SEM, two-tailed unpaired t-test.
