Nuclear FAK in endothelium: An intrinsic inhibitor of NF-κB activation in atherosclerosis

Hyperlipidemia leads to the accumulation of oxidized low-density lipoprotein (oxLDL) within the vessel wall where it causes chronic inflammation in endothelial cells (ECs) and drives atherosclerotic lesions. Although focal adhesion kinase (FAK) is critical in proinflammatory NF-κB activation in ECs, it is unknown if hyperlipidemia alters FAK-mediated NF-κB activity in vivo to affect atherosclerosis progression.

Hyperlipidemia leads to the accumulation of oxidized low-density lipoprotein (oxLDL) within the vessel wall where it causes chronic inflammation in endothelial cells (ECs) and drives atherosclerotic lesions. Although focal adhesion kinase (FAK) is critical in proinflammatory NF-κB activation in ECs, it is unknown if hyperlipidemia alters FAK-mediated NF-κB activity in vivo to affect atherosclerosis progression.

Hyperlipidemic conditions activate NF-κB pathway by increasing EC FAK activity and cytoplasmic localization in mice and human atherosclerotic samples. As FAK inhibition can efficiently reduce vascular inflammation and atherosclerotic lesions in mice by reversing EC FAK localization and NF-κB activation, these findings support a potential use for FAK inhibitors in treating atherosclerosis.

We investigated changes in EC FAK and NF-κB activation using Apoe-/- mice fed a western diet (WD). Both pharmacological FAK inhibition and EC-specific FAK inhibited mouse models were utilized. FAK and NF-κB localization and activity were also analyzed in human atherosclerotic samples.

ECs of hyperlipidemic mice clearly showed much higher levels of FAK activation in the cytoplasm, which was associated with increased NF-κB activation compared to normal diet (ND) group. On the contrary, FAK is mostly localized in the nucleus and inactive in ECs under healthy conditions with a low NF-κB activity. Both pharmacological and EC-specific genetic FAK inhibition in WD fed Apoe-/- mice exhibited a significant decrease in FAK activity and cytoplasmic localization, NF-κB activation, macrophage recruitment, and atherosclerotic lesions compared to the vehicle or FAK wild-type groups. Analyses of human atherosclerotic specimens revealed a positive correlation between increased active cytoplasmic FAK within ECs and NF-κB activation in the lesions. Conclusions: Hyperlipidemic conditions activate NF-κB pathway by increasing EC FAK activity and cytoplasmic localization in mice and human atherosclerotic samples. As FAK inhibition can efficiently reduce vascular inflammation and atherosclerotic lesions in mice by reversing EC FAK localization and NF-κB activation, these findings support a potential use for FAK inhibitors in treating atherosclerosis.