Project Details
Description
PROJECT SUMMARY
Studies in the mouse model of oxygen-induced retinopathy (OIR) have shown that macrophage-
induced angiogenesis has a critical role in pathological retinal neovascularization (RNV) but the
mechanisms are not yet known. We propose to investigate expression/activity of the cholesterol
metabolizing enzyme ACAT (acyl-Coenzyme A: cholesterol acyltransferase, also known as sterol
O-acyltranserase) as a novel therapeutic target for RNV. There are two isoforms of ACAT: ACAT1
and ACAT2. ACAT1 is widely expressed and its upregulation in macrophages or
macrophage/microglia has been implicated in atherosclerosis and Alzheimer's disease,
respectively. ACAT2 is mainly expressed in the intestines and liver. We will focus on ACAT1 in
this project. During ischemia/hypoxia, macrophages are exposed to increased levels of oxidized
low density lipoprotein cholesterol (oxLDLc). Its internalization by the LDL receptor (LDLR)
increases activity of ACAT1, which esterifies cholesterol to form cholesterol esters (CE).
Increases in CE promote an inflammatory macrophage phenotype characterized by increased
expression of the amplifier of inflammatory signaling TREM-1 (triggering receptor expressed in
myeloid cells-1), MCSF (macrophage colony stimulating factor), VEGF and TNFα. Our preliminary
studies in the mouse OIR model show marked increases in lipid accumulation, LDLR expression
and CE formation in areas of RNV suggesting that dyslipidemia and ACAT activity play a key role
in RNV. Furthermore, LDLR deletion or ACAT inhibition prevented RNV and decreased
expression of TREM-1, MCSF and VEGF. Moreover, hypoxia treatment of macrophages in vitro
significantly increased their expression of TREM-1, MCSF and VEGF. Based on these results our
central hypothesis is that LDLc-induced increases in ACAT1 and CE formation drive
macrophage activation and pathological RNV in the mouse model of OIR (Fig. 1). Our aims
will test this hypothesis by determining whether 1) Inhibition of ACAT1 prevents RNV in vivo, 2)
Deletion of ACAT1 in myeloid derived cells prevents RNV in vivo and MΦ -induced angiogenesis
in vitro.
Status | Not started |
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