June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Is acyl-coenzyme A: cholesterol transferase (ACAT1) a mediator of neurovascular injury in diabetic retinopathy?
Author Affiliations & Notes
  • MODESTO ANTONIO ROJAS
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
    James & Jean Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, United States
  • Syed Adeel Zaidi
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
    James & Jean Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, United States
  • Tahira Lemtalsi
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
    James & Jean Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, United States
  • Zhimin Xu
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
    James & Jean Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, United States
  • Porsche Sandow
    Pharmacology, Augusta University, Augusta, Georgia, United States
    James & Jean Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, United States
  • R William Caldwell
    Pharmacology, Augusta University, Augusta, Georgia, United States
    James & Jean Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, United States
  • Ruth B Caldwell
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
  • Footnotes
    Commercial Relationships   MODESTO ROJAS None; Syed Zaidi None; Tahira Lemtalsi None; Zhimin Xu None; Porsche Sandow None; R Caldwell None; Ruth Caldwell None
  • Footnotes
    Support  R21EY032265
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3776. doi:
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      MODESTO ANTONIO ROJAS, Syed Adeel Zaidi, Tahira Lemtalsi, Zhimin Xu, Porsche Sandow, R William Caldwell, Ruth B Caldwell; Is acyl-coenzyme A: cholesterol transferase (ACAT1) a mediator of neurovascular injury in diabetic retinopathy?. Invest. Ophthalmol. Vis. Sci. 2023;64(8):3776.

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

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Abstract

Purpose : Diabetic retinopathy (DR) is a leading cause of vision loss. Current treatments target late-stage disease. Our goal is to identify a new therapy to limit dysfunction prior to tissue damage by targeting the cholesterol metabolizing enzyme ACAT1. In DR, hyperglycemic stress induces an inflammatory phenotype leading to neurovascular injury. DR has also been correlated with high cholesterol but cholesterol’s role in the pathology is unknown. ACAT1 metabolizes cholesterol to form cholesterol ester (CE) and is expressed in microglia, macrophages, and photoreceptors. Our studies in the mouse model of oxygen-induced retinopathy have shown that increases in ACAT1 and CE formation promote increases in the inflammation amplifying factor TREM-1 and its downstream targets. Inhibiting ACAT1 reduces this inflammatory response and limits retinal neovascularization. Here we investigate the role of ACAT1 in neurovascular damage during DR.

Methods : Our studies used retinas from human donors, surgical vitrectomy samples, Ins2 Akita mice, and WT controls. Akita mice were treated with a specific ACAT1 inhibitor (10mg/Kg) or vehicle for 2 wks. At 12 wks mice were tested for OptoMotry and ERG. Retinas were collected for assays of lipid peroxidation (4HNE), CE formation (filipin staining), immunolocalization, and western blot. Other groups were assayed for leukostasis, permeability, and acellular capillaries

Results : DR patient samples showed increased expression of ACAT1 on photoreceptors as compared to controls. ACAT1 was also expressed in F4/80 and TREM-1 double positive cells in vitreoretinal membranes from DR patients. Retinas of Ins2 Akita mice showed increases in LDLR, ACAT1, TREM-1, VEGF, and TNF-α vs controls (P<0.05), along with increases in 4HNE, CE formation, leukostasis, permeability, and acellular capillary formation (P<0.05). ERG, visual acuity, and contrast sensitivity were reduced (P<0.05). Treatment with the ACAT1 inhibitor significantly abrogated all these changes (P<0.05).

Conclusions : In DR, neurovascular damage is associated with increases in ACAT1, CE formation and lipid peroxidation along with upregulation of TREM-1, M-CSF, VEGF, LDLR, and TNF-α. Inhibiting ACAT1 blocks these effects, indicating that targeting this pathway offers a novel strategy for treatment and prevention of early neurovascular damage during DR.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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