TY - JOUR
T1 - Role of acyl-coenzyme A
T2 - cholesterol transferase 1 (ACAT1) in retinal neovascularization
AU - Zaidi, Syed A.H.
AU - Lemtalsi, Tahira
AU - Xu, Zhimin
AU - Santana, Isabella
AU - Sandow, Porsche
AU - Labazi, Leila
AU - Caldwell, Robert William
AU - Caldwell, Ruth B
AU - Rojas, Modesto Antonio
N1 - Funding Information:
This study was supported by grants from the National Institute of Health [R21EY032265 (MAR and RBC), R01EY011766 (RBC and RWC), R01EY030500] and the Culver Vision Discovery Institute [P30EY031631] at Augusta University.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - Background: We have investigated the efficacy of a new strategy to limit pathological retinal neovascularization (RNV) during ischemic retinopathy by targeting the cholesterol metabolizing enzyme acyl-coenzyme A: cholesterol transferase 1 (ACAT1). Dyslipidemia and cholesterol accumulation have been strongly implicated in promoting subretinal NV. However, little is known about the role of cholesterol metabolism in RNV. Here, we tested the effects of inhibiting ACAT1 on pathological RNV in the mouse model of oxygen-induced retinopathy (OIR). Methods: In vivo studies used knockout mice that lack the receptor for LDL cholesterol (LDLR−/−) and wild-type mice. The wild-type mice were treated with a specific inhibitor of ACAT1, K604 (10 mg/kg, i.p) or vehicle (PBS) during OIR. In vitro studies used human microglia exposed to oxygen–glucose deprivation (OGD) and treated with the ACAT1 inhibitor (1 μM) or PBS. Results: Analysis of OIR retinas showed that increased expression of inflammatory mediators and pathological RNV were associated with significant increases in expression of the LDLR, increased accumulation of neutral lipids, and formation of toxic levels of cholesterol ester (CE). Deletion of the LDLR completely blocked OIR-induced RNV and significantly reduced the AVA. The OIR-induced increase in CE formation was accompanied by significant increases in expression of ACAT1, VEGF and inflammatory factors (TREM1 and MCSF) (p < 0.05). ACAT1 was co-localized with TREM1, MCSF, and macrophage/microglia makers (F4/80 and Iba1) in areas of RNV. Treatment with K604 prevented retinal accumulation of neutral lipids and CE formation, inhibited RNV, and decreased the AVA as compared to controls (p < 0.05). The treatment also blocked upregulation of LDLR, ACAT1, TREM1, MCSF, and inflammatory cytokines but did not alter VEGF expression. K604 treatment of microglia cells also blocked the effects of OGD in increasing expression of ACAT1, TREM1, and MCSF without altering VEGF expression. Conclusions: OIR-induced RNV is closely associated with increases in lipid accumulation and CE formation along with increased expression of LDLR, ACAT1, TREM1, and MCSF. Inhibiting ACAT1 blocked these effects and limited RNV independently of alterations in VEGF expression. This pathway offers a novel strategy to limit vascular injury during ischemic retinopathy. Graphical Abstract: [Figure not available: see fulltext.]
AB - Background: We have investigated the efficacy of a new strategy to limit pathological retinal neovascularization (RNV) during ischemic retinopathy by targeting the cholesterol metabolizing enzyme acyl-coenzyme A: cholesterol transferase 1 (ACAT1). Dyslipidemia and cholesterol accumulation have been strongly implicated in promoting subretinal NV. However, little is known about the role of cholesterol metabolism in RNV. Here, we tested the effects of inhibiting ACAT1 on pathological RNV in the mouse model of oxygen-induced retinopathy (OIR). Methods: In vivo studies used knockout mice that lack the receptor for LDL cholesterol (LDLR−/−) and wild-type mice. The wild-type mice were treated with a specific inhibitor of ACAT1, K604 (10 mg/kg, i.p) or vehicle (PBS) during OIR. In vitro studies used human microglia exposed to oxygen–glucose deprivation (OGD) and treated with the ACAT1 inhibitor (1 μM) or PBS. Results: Analysis of OIR retinas showed that increased expression of inflammatory mediators and pathological RNV were associated with significant increases in expression of the LDLR, increased accumulation of neutral lipids, and formation of toxic levels of cholesterol ester (CE). Deletion of the LDLR completely blocked OIR-induced RNV and significantly reduced the AVA. The OIR-induced increase in CE formation was accompanied by significant increases in expression of ACAT1, VEGF and inflammatory factors (TREM1 and MCSF) (p < 0.05). ACAT1 was co-localized with TREM1, MCSF, and macrophage/microglia makers (F4/80 and Iba1) in areas of RNV. Treatment with K604 prevented retinal accumulation of neutral lipids and CE formation, inhibited RNV, and decreased the AVA as compared to controls (p < 0.05). The treatment also blocked upregulation of LDLR, ACAT1, TREM1, MCSF, and inflammatory cytokines but did not alter VEGF expression. K604 treatment of microglia cells also blocked the effects of OGD in increasing expression of ACAT1, TREM1, and MCSF without altering VEGF expression. Conclusions: OIR-induced RNV is closely associated with increases in lipid accumulation and CE formation along with increased expression of LDLR, ACAT1, TREM1, and MCSF. Inhibiting ACAT1 blocked these effects and limited RNV independently of alterations in VEGF expression. This pathway offers a novel strategy to limit vascular injury during ischemic retinopathy. Graphical Abstract: [Figure not available: see fulltext.]
KW - ACAT1
KW - Cholesterol ester
KW - Cytokines
KW - Hypoxia
KW - Inflammation
KW - LDL cholesterol
KW - Neovascularization
KW - Oxygen-induced retinopathy
KW - Retinopathy of prematurity
KW - TREM1
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U2 - 10.1186/s12974-023-02700-5
DO - 10.1186/s12974-023-02700-5
M3 - Article
C2 - 36691048
AN - SCOPUS:85146792365
SN - 1742-2094
VL - 20
JO - Journal of Neuroinflammation
JF - Journal of Neuroinflammation
IS - 1
M1 - 14
ER -