Atherosclerosis arises as a result of excess accumulation of cholesterol within vascular cells, with
macrophages comprising a majority of these lipid-laden foam cells within atherosclerotic lesions. Lipid-lowering
therapies, such as statins, have proven beneficial, but still only benefit a subset of patients. As such, there is
currently a need to develop new treatment options that can treat a larger portion of atherosclerosis patients to
reduce cardiovascular disease mortality. One potential strategy for treating atherosclerosis is to reduce foam
cells by decreasing cholesterol uptake (influx) and/or to promote cholesterol release (efflux) in macrophages.
However, no current therapy targets these mechanisms. Foam cells within atherosclerotic lesions are
developed from too much cholesterol influx without efficient efflux. Focal adhesion kinase (FAK) is an integrin-
associated tyrosine kinase which contributes to vascular cell migration, proliferation, and inflammation. We
have discovered new functions for FAK in the regulation of lipid homeostasis within macrophages. Our
preliminary data revealed that FAK activation following oxidized low-density lipoprotein (oxLDL) stimulation
was required for foam cell formation via endocytosis of CD36. Additionally, oxLDL increased FAK interaction
with CD36 and Filamin A. Importantly, pharmacological FAK inhibition blocked FAK-CD36-Filamin A interaction
and subsequent foam cell formation, suggesting that the ternary complex may contribute to oxLDL uptake.
More interestingly, FAK inhibition increased expression of cellular lipid sensors peroxisome proliferator
activated receptor g (PPARg) and liver X receptor a (LXRa) resulting in increased transcription of the
cholesterol antiporters ABCG1 and ABCA1. FAK inhibition also increased PPARg and LXRa nuclear
translocation, and this was associated with decreased expression of nuclear receptor corepressor 2 (NCOR2).
In a new macrophage-specific FAK kinase-dead (KD) mouse model (CSF1R-iCre) on ApoE-/- background, we
observed that FAK-KD mice fed a western diet (WD) showed less foam cell formation and reduced
atherosclerotic lesions. Taken together, our central hypothesis is that FAK inhibition reduces oxLDL uptake via
disruption of FAK-Filamin A-CD36 complex formation while also increasing cholesterol efflux through increased
PPARg and LXRa activation via NCOR2 degradation. To decipher a molecular mechanism in which a two-fold
role of FAK prevents cholesterol uptake as well as enhances efflux in macrophages. Aim 1 will determine FAK
and Filamin A regulation of oxLDL-CD36 uptake in macrophages. Aim 2 will investigate FAK regulation of
cholesterol efflux via PPARg and LXRa activation in foam cells. Aim 3 will evaluate the effect of FAK inhibition
on preventive and therapeutic models of atherosclerosis. The proposed study will shed new insights on the role
of FAK in cholesterol homeostasis in macrophage foam cells and could produce a new treatment option in
atherosclerosis by reducing the foam cells via reduced cholesterol influx and elevated cholesterol efflux.