Abstract
<jats:p><p dir="ltr">Endothelial dysfunction contributes to the pathogenesis/progression of diabetes and atherosclerotic cardiovascular diseases (ASCVDs) with Sirtuin-6 (SIRT6) downregulation in vascular endothelial cells (ECs). This study aimed to investigate the effects and underlying mechanisms of SIRT6 as a deacetylase in maintaining EC integrity against diabetes-exacerbated atherogenesis. SIRT6 downregulation was exacerbated in carotid artery ECs of STZ-induced-diabetic/HFD-fed and PCL-induced-atherosclerotic <i>Apoe</i><sup>-/-</sup> mice, which had aggravated atherosclerotic plaque formation. Further study showed <i>SIRT6</i> knockdown aggravated advanced glycation end-products (AGEs)-induced EC monolayer hyperpermeability, while <i>SIRT6</i> overexpression exerted opposite protective effects. Moreover, exacerbated atherosclerosis progression with greater vascular hyperpermeability was observed in EC-specific <i>Sirt6</i> knockout mice. Co-IP/mass-spectrometry identified SIRT6 interacting with zinc-finger E-box binding homeobox 1 (ZEB1) for deacetylation/degradation, maintaining ZEB1 at low level for normal expression of tight junction protein Claudin-1 (CLDN1) in ECs. SIRT6 deficiency reduced ZEB1 deacetylation to inhibit CLDN1 expression, which impaired EC integrity, promoted monocyte/macrophage infiltration and exacerbated atherosclerosis. Finally, Naringin, a natural ZEB1 inhibitor, was observed to reverse EC-<i>Sirt6</i>-knockout-mediated ZEB1 accumulation, restore CLDN1 expression and improve vascular hyperpermeability, which reduced monocyte/macrophage accumulation and attenuated atherosclerosis progression. Conclusively, SIRT6 regulation of ZEB1 deacetylation/degradation for EC-CLDN1 expression advances understanding of diabetes-exacerbated atherosclerosis; meanwhile, it provides a novel therapeutic target for intervention of diabetic ASCVDs.</p></jats:p>