The crosstalk between Nrf2 and NF-κB pathways in coronary artery disease: Can it be regulated by SIRT6?

Coronary artery disease (CAD) is the leading cause of death worldwide. Oxidative stress and inflammation are major mechanisms responsible for the progression of CAD. Nuclear transcription factor erythroid-2 related factor 2 (Nrf2) is a transcription factor that modulates the cellular redox status. Nrf2 upregulation increases the expression of antioxidant genes, decreases the expression of Nuclear factor-kappa B (NF-kB), and increases free radical metabolism. Activated NF-kB increases the production of inflammatory cytokines causing endothelial dysfunction. The two pathways of Nrf2 and NF-kB can regulate the expression of each other. Foremost, the Nrf2 pathway can decrease the level of active NF-κB by increasing the level of antioxidants and cytoprotective enzymes. Furthermore, the Nrf2 pathway prevents IκB-α degradation, an inhibitor of NF-kB, and thus inhibits NF-κB mediated transcription. Also, NF-kB transcription inhibits Nrf2 activation by reducing the antioxidant response element (ARE) transcription. Sirtuin 6 (SIRT6) is a member of the Sirtuins family that was found to protect against cardiovascular diseases. SIRT6 can suppress the production of Reactive oxygen species (ROS) through deacetylation of NRF2 which results in NRF2 activation. Furthermore, SIRT6 can inhibit the inflammatory process through the downregulation of NF-kB transcription. Therefore, targeting sirtuins could be a therapeutic strategy to treat CAD. This review describes the potential role of SIRT6 in regulating the crosstalk between NRF2 and NF-kB signaling pathways in CAD.