SIRT6 mediates MRTF-A deacetylation in vascular endothelial cells to antagonize oxLDL-induced ICAM-1 transcription

Oxidized low-density lipoprotein (oxLDL), a known risk factor for atherosclerosis, activates the transcription of adhesion molecules (ICAM-1) in endothelial cells. We previously showed that myocardin-related transcription factor A (MRTF-A) mediates oxLDL-induced ICAM-1 transcription. Here we confirm that ICAM-1 transactivation paralleled dynamic alterations in MRTF-A acetylation. Since treatment with the antioxidant NAC dampened MRTF-A acetylation, MRTF-A acetylation appeared to be sensitive to cellular redox status. Of interest, silencing of SIRT6, a lysine deacetylase, restored MRTF-A acetylation despite the addition of NAC. SIRT6 directly interacted with MRTF-A to modulate MRTF-A acetylation. Deacetylation of MRTF-A by SIRT6 led to its nuclear expulsion thus dampening MRTF-A occupancy on the ICAM-1 promoter. Moreover, SIRT6 expression was downregulated with oxLDL stimulation likely owing to promoter hypermethylation in endothelial cells. DNA methyltransferase 1 (DNMT1) was recruited to the SIRT6 promoter and mediated SIRT6 repression. The ability of DNMT1 to repress SIRT6 promoter partly was dependent on ROS-sensitive serine 154 phosphorylation. In conclusion, our data unveil a novel DNMT1-SIRT6 axis that contributes to the regulation of MRTF-A acetylation and ICAM-1 transactivation in endothelial cells.

Automated summary

The findings of this study demonstrate that oxidized low-density lipoprotein (oxLDL) activates the transcription of adhesion molecules in endothelial cells and leads to dynamic changes in the acetylation of myocardin-related transcription factor A (MRTF-A). The acetylation status of MRTF-A appears to be sensitive to cellular redox status, as treatment with the antioxidant NAC reduces its acetylation. Silencing of the lysine deacetylase SIRT6 restores MRTF-A acetylation despite NAC treatment, suggesting that SIRT6 plays a role in modulating MRTF-A acetylation. SIRT6 interacts with MRTF-A and promotes its deacetylation, leading to its expulsion from the nucleus and reduced occupancy on the ICAM-1 promoter. Furthermore, SIRT6 expression is downregulated with oxLDL stimulation due to promoter hypermethylation mediated by DNA methyltransferase 1 (DNMT1), which is recruited to the SIRT6 promoter and represses its expression. The ability of DNMT1 to repress SIRT6 expression is partly dependent on ROS-sensitive serine 154 phosphorylation.