| Autor: |
Syed Zaidi, Tahira Lemtalsi, Zhimin Xu, Isabella Santana, Porsche Sandow, Leila Labazi, Robert W. Caldwell, Ruth B. Caldwell, Modesto A. Rojas |
| Rok vydání: |
2022 |
| DOI: |
10.21203/rs.3.rs-1972381/v1 |
| Popis: |
Background: We have investigated the efficacy of a new strategy to limit pathological retinal neovascularization (RNV) during ischemic retinopathy. Our previous studies in a mouse model of oxygen-induced retinopathy (OIR) showed that blockade of a receptor of the immunoglobulin superfamily, triggering receptor expressed on myeloid cells 1 (TREM1) significantly inhibited RNV and reduced expansion of the avascular area (AVA). Here we investigated the role of the cholesterol metabolizing enzyme acyl-coenzyme A: cholesterol transferase 1 (ACAT1) in this process.Methods: In vivo studies used the mouse model of OIR using LDLR-/- mice and wild-type mice treated with a specific inhibitor of ACAT1 (10 mg/Kg, i.p) or vehicle (PBS). In vitro studies used human THP1 macrophages maintained in hypoxia (1% O2) or normoxia (21% O2) for 16 hrs and treated with the ACAT1 inhibitor (10μg/ml) 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 LDL receptor (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) (pConclusions: 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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