Targeting HDAC3 in the DBA/2J spontaneous mouse model of glaucoma

Schmitt, H; Grosser, Joshua A; Schlamp, Cassandra L.; Nickells, Robert W.

doi:10.1016/j.exer.2020.108244

Cited by 13 publications

(8 citation statements)

References 41 publications

(60 reference statements)

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“…HDAC3 was also reported to be related to retinal neurodegeneration and could be a potential threat target. HDAC3 overexpression could increase the sensitivity of retinal neurons to axonal damage [ 16 ], and HDAC3 inhibition would alleviate high intraocular pressure-induced RGC loss in the DBA/2J mouse model of glaucoma [ 23 ]. DR-related neurodegeneration was studied using the DB/DB mice, and it was found that HDAC3 was closely related to injury repair and nerve regeneration [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

HDAC3 Inhibition Alleviates High-Glucose-Induced Retinal Ganglion Cell Death through Inhibiting Inflammasome Activation

Tang

Liu

et al. 2022

BioMed Research International

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Purpose. The exact effects of histone deacetylase 3 (HDAC3) inhibition in DR related retinal ganglion cells (RGCs) death remained unclear. This study is aimed at detecting the influence of HDAC3 on the high-glucose-induced retinal ganglion cell death. Methods. The retinal HDAC3 expression in DR of different time points was analyzed by immunohistochemical assay and western blot. Besides, the expression of HDAC3 and both retinal thickness and RGC loss were analyzed. The effects of HDAC3 inhibitor on cell viability, oxidative stress, and apoptosis in high-glucose- (HG-) treated RGCs were analyzed. Both inflammatory and antioxidative factors were detected by ELISA. Results. Advanced effects of HDAC3 inhibition on the expression of NLRP3 inflammasome were detected using western blots. High HDAC3 expression was detected only in the late DR mice (4 months of diabetes duration) but not early DR mice (2 months of diabetes duration). The immunohistochemical assay showed that HDAC3 expression was correlated with both retinal thickness and RCG contents. HDAC3 inhibitor significantly protected the HG-treated RGCs from damaged cell viability, severe apoptosis, and oxidative stress. Advanced pathway analyses showed that HDAC3 inhibition inactivated NLRP3 inflammasome and thus alleviated retinal inflammation. Conclusion. In conclusion, HDAC3 was involved in RGC loss and thus promoted the progression of neurodegeneration of DR. Besides, HDAC3 inhibitor demonstrated protective effects in neurodegeneration in DR through downregulation of NLRP3 activity. The effects of HDAC3 inhibitor in DR management should be confirmed in clinical trials.

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Section: Discussionmentioning

confidence: 99%

HDAC3 Inhibition Alleviates High-Glucose-Induced Retinal Ganglion Cell Death through Inhibiting Inflammasome Activation

Tang

Liu

et al. 2022

BioMed Research International

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“…Each cohort contained 5 male and 5 female mice. IOPs were measured every 2 weeks between 9 and 11 a.m. using a Tonolab rebound tonometer (Icare, Finland) as previously described [ 35 ]. Eyes that developed corneal abnormalities were excluded.…”

Section: Methodsmentioning

confidence: 99%

“…Each cohort of glaucomatous mice contained at least 49 ONs and 29 retinas. We did not use a control viral injection because other studies have found no effect on IOP progression or protection of RGCs by control AAVs [ 35 , 36 ]. Because glaucomatous disease progresses asymmetrically in the eyes of DBA/2J mice [ 21 ], each eye/retina/ON was considered as an independent variable.…”

Section: Methodsmentioning

confidence: 99%

BCLXL gene therapy moderates neuropathology in the DBA/2J mouse model of inherited glaucoma

et al. 2021

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Axonal degeneration of retinal ganglion cells (RGCs) causes blindness in glaucoma. Currently, there are no therapies that target axons to prevent them from degenerating. Activation of the BAX protein has been shown to be the determining step in the intrinsic apoptotic pathway that causes RGCs to die in glaucoma. A putative role for BAX in axonal degeneration is less well elucidated. BCLXL (BCL2L1) is the primary antagonist of BAX in RGCs. We developed a mCherry-BCLXL fusion protein, which prevented BAX recruitment and activation to the mitochondria in tissue culture cells exposed to staurosporine. This fusion protein was then packaged into adeno-associated virus serotype 2, which was used to transduce RGCs after intravitreal injection and force its overexpression. Transduced RGCs express mCherry-BCLXL throughout their somas and axons along the entire optic tract. In a model of acute optic nerve crush, the transgene prevented the recruitment of a GFP-BAX fusion protein to mitochondria and provided long-term somal protection up to 12 weeks post injury. To test the efficacy in glaucoma, DBA/2J mice were transduced at 5 months of age, just prior to the time they begin to exhibit ocular hypertension. Gene therapy with mCherry-BCLXL did not affect the longitudinal history of intraocular pressure elevation compared to naive mice but did robustly attenuate both RGC soma pathology and axonal degeneration in the optic nerve at both 10.5 and 12 months of age. BCLXL gene therapy is a promising candidate for glaucoma therapy.

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“…Scale bar = 20 mm. Figure adapted from Ref 52 . HDAC1 indicates histone deacetylase 1; GCL, ganglion cell layer; GFAP, glial fibrillary acidic protein; LSD1, lysine-specific demethylase 1; ONL, outer nuclear layer; WT, wild type.…”

Section: The Potential Of Epigenetic Therapy In Eye Diseasementioning

confidence: 99%

“…51 Inhibition of HDAC3 gave some protection against ganglion cell death in the DBA/2J model of pigmentary glaucoma, suggesting that these enzymes may be damaging rather than part of a protective response. 52…”

Section: Epigenetic Modifications In Retinal Degenerative Diseasesmentioning

confidence: 99%

Epigenetics and Degenerative Retinal Diseases: Prospects for New Therapeutic Approaches

Barnstable

2022

Asia-Pacific Journal of Ophthalmology

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There is growing evidence that retinal degenerative diseases are accompanied by epigenetic changes in both deoxyribonucleic acid methylation and histone modification. Even in the monogenic disease retinitis pigmentosa, there is a cascade of changes in gene expression that correlate with epigenetic changes, suggesting that many of the symptoms, and degenerative changes, may be a result of epigenetic changes downstream from the genetic mutation. This is supported by data from studies of diabetic retinopathy and macular degeneration, 2 diseases where it has been difficult to define a single causative change. Initial studies with modifiers of deoxyribonucleic acid methylation suggest that they can provide therapeutic benefit. A number of drugs are available to inhibit specific epigenetic histone modifier enzymes, and these offer the possibility of new therapeutic approaches to retinal disease. Systemic treatment with inhibitors of histone demethylases and histone deacetylases have arrested rod degeneration in rodent models of retinitis pigmentosa. Some evidence has suggested that similar treatments may provide benefits for patients with diabetic retinopathy. Because differentiation of retinal stem cells is regulated in part by epigenetic mechanisms, it may also be possible to direct stem cell differentiation pathways through the use of selective epigenetic modifiers. This is predicted to provide a valuable avenue to accelerate the introduction of regenerative approaches to retinal disease. Epigenetic modifiers are poised to become a powerful new approach to treat retinal degenerative diseases.

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Targeting HDAC3 in the DBA/2J spontaneous mouse model of glaucoma

Cited by 13 publications

References 41 publications

HDAC3 Inhibition Alleviates High-Glucose-Induced Retinal Ganglion Cell Death through Inhibiting Inflammasome Activation

HDAC3 Inhibition Alleviates High-Glucose-Induced Retinal Ganglion Cell Death through Inhibiting Inflammasome Activation

BCLXL gene therapy moderates neuropathology in the DBA/2J mouse model of inherited glaucoma

Epigenetics and Degenerative Retinal Diseases: Prospects for New Therapeutic Approaches

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