Myeloid ACAT1 in ischemic retinopathy

Myeloid ACAT1 in Ischemic Retinopathy
Studies in the mouse models of oxygen-induced retinopathy (OIR) and diabetic retinopathy (DR) have shown
that myeloid cell-induced angiogenesis has a critical role in pathological retinal neovascularization (RNV) and
retinal neurovascular dysfunction/injury, but the mechanisms are not yet known. We propose to investigate
myeloid cell 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 ischemic retinopathy.
There are two isoforms of ACAT: ACAT1 and ACAT2. ACAT1 is widely expressed and its upregulation in
macrophages and 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, microglia/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 microglia/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
studies in the mouse model of OIR 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 and MCSF. Our studies
in DR mice show similar signs of dyslipidemia and ACAT1 activation associated with DR-induced retinal
inflammation and neurovascular injury. Moreover, hypoxia treatment of microglia/macrophages in vitro
significantly increased their expression of TREM-1 and MCSF. Based on these results our central hypothesis is
that ischemia-induced activation of ACAT1 drives retinal inflammation and promotes neurovascular
injury during OIR and DR. Our aims will test this hypothesis by determining whether 1) ACAT1-mediated
activation of Mg/MΦ cells is critically involved in OIR-induced RNV and neuroglial injury/dysfunction, 2) DR-
induced ACAT1 activation in Mg/MΦ cells promotes retinal neurovascular injury/dysfunction.

Grant Number: 5R01EY035683-02
NIH Institute/Center: NIH
Principal Investigator: Ruth Caldwell