June 2020
Volume 61, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2020
Neuronal Epac1 mediates retinal neurodegeneration in mouse models of ocular hypertension
Author Affiliations & Notes
  • Fan Xia
    Ophthalmology & Visual Sciences, University of Texas Medical Branch, Galveston, Texas, United States
  • Wei Liu
    Ophthalmology & Visual Sciences, University of Texas Medical Branch, Galveston, Texas, United States
  • Yonju Ha
    Ophthalmology & Visual Sciences, University of Texas Medical Branch, Galveston, Texas, United States
  • Shuang Zhu
    Ophthalmology & Visual Sciences, University of Texas Medical Branch, Galveston, Texas, United States
  • Yi Li
    Ophthalmology & Visual Sciences, University of Texas Medical Branch, Galveston, Texas, United States
  • Shuizhen Shi
    Ophthalmology & Visual Sciences, University of Texas Medical Branch, Galveston, Texas, United States
  • Fang C Mei
    Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, University of Texas Health Science Center at Houston, Texas, United States
  • Kevin H. Merkley
    Ophthalmology & Visual Sciences, University of Texas Medical Branch, Galveston, Texas, United States
  • Gianmarco Vizzeri
    Ophthalmology & Visual Sciences, University of Texas Medical Branch, Galveston, Texas, United States
  • Massoud Motamedi
    Ophthalmology & Visual Sciences, University of Texas Medical Branch, Galveston, Texas, United States
  • Xiaodong Cheng
    Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, University of Texas Health Science Center at Houston, Texas, United States
  • Hua Liu
    Ophthalmology & Visual Sciences, University of Texas Medical Branch, Galveston, Texas, United States
  • Wenbo Zhang
    Ophthalmology & Visual Sciences, University of Texas Medical Branch, Galveston, Texas, United States
    Department of Neuroscience, Cell Biology & Anatomy, University of Texas Medical Branch, Galveston, Galveston, Texas, United States
  • Footnotes
    Commercial Relationships   Fan Xia, None; Wei Liu, None; Yonju Ha, None; Shuang Zhu, None; Yi Li, None; Shuizhen Shi, None; Fang C Mei, None; Kevin Merkley, None; Gianmarco Vizzeri, None; Massoud Motamedi, None; Xiaodong Cheng, None; Hua Liu, None; Wenbo Zhang, None
  • Footnotes
    Support  This work was supported by National Institutes of Health grant EY022694 and Retina Research Foundation (to W.Z.), American Heart Association 17SDG33630151 (to H.L.), and National Institutes of Health grant GM122536 (to X.C.)
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 1264. doi:
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      Fan Xia, Wei Liu, Yonju Ha, Shuang Zhu, Yi Li, Shuizhen Shi, Fang C Mei, Kevin H. Merkley, Gianmarco Vizzeri, Massoud Motamedi, Xiaodong Cheng, Hua Liu, Wenbo Zhang; Neuronal Epac1 mediates retinal neurodegeneration in mouse models of ocular hypertension. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1264.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Glaucoma is characterized by progressive loss of retinal ganglion cells (RGCs), resulting in irreversible visual deficits. Cyclic AMP (cAMP) is a universal second messenger that regulates many pathophysiological processes. Yet the role of cAMP and its downstream mediators in neurodegeneration in glaucoma are largely unknown. Exchange protein activated by cAMP (Epac) is a newly identified mediator of cAMP. Here, we assessed the role of cAMP/Epac1 pathway in RGC injury in two mouse models of ocular hypertension.

Methods : Mouse model of retinal ischemia-reperfusion (IR) was induced by increasing the intraocular pressure (IOP) to 110 mm Hg to block retinal blood flow for 45 minutes followed by restoring normal IOP to allow reperfusion. Microbead-induced glaucoma model was induced by injecting polystyrene microbeads into anterior chamber to inhibit the drainage of aqueous humor, resulting in a moderate but sustained increase in IOP similar to that in chronic glaucoma.

Results : The level of cAMP and the activity and expression of Epac1 were increased in retinas of two mouse models. Genetic depletion of Epac1 significantly attenuated ocular hypertension-induced detrimental effects in the retina, including vascular inflammation, neuronal apoptosis and necroptosis, thinning of ganglion cell complex layer, RGC loss and retinal neuronal dysfunction. With bone marrow transplantation and various Epac1 conditional knockout mice, we further demonstrated that Epac1 in retinal neuronal cells (especially RGCs) was responsible for their death. Consistently, pharmacologic inhibition of Epac activity prevented RGC loss. Moreover, in vitro study on primary RGCs showed that Epac1 activation was sufficient to induce RGC death, which was mechanistically mediated by CaMKII activation.

Conclusions : These findings indicate neuronal Epac1 plays a critical role in retinal neurodegeneration and suggest that Epac1 could be considered a target for neuroprotection in glaucoma.

This is a 2020 ARVO Annual Meeting abstract.

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