Abstract
Endothelial dysfunction contributes to the pathogenesis and progression of diabetes and atherosclerotic cardiovascular diseases (ASCVDs) with sirtuin-6 (SIRT6) downregulation in vascular endothelial cells (ECs). Here, the effects and underlying mechanisms of SIRT6 as a deacetylase were investigated in maintaining EC integrity against diabetes-exacerbated atherogenesis. SIRT6 downregulation was exacerbated in carotid artery ECs of Apoe−/− mice with streptozotocin (STZ)-induced diabetes that were fed a high-fat diet and had partial carotid ligation-induced atherosclerosis, which had aggravated atherosclerotic plaque formation. Further study showed SIRT6 knockdown aggravated advanced glycation end products–induced EC-monolayer hyperpermeability, whereas SIRT6 overexpression exerted opposite protective effects. Moreover, exacerbated atherosclerosis progression with greater vascular hyperpermeability was observed in EC-specific Sirt6 knockout mice. Co-immunoprecipitation/mass spectrometry identified SIRT6 interacting with zinc-finger E-box binding homeobox 1 (ZEB1) for deacetylation and degradation, maintaining ZEB1 at a 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, reversed EC–Sirt6-knockout–mediated ZEB1 accumulation, restored CLDN1 expression, and improved vascular hyperpermeability, which reduced monocyte/macrophage accumulation and attenuated atherosclerosis progression. Conclusively, SIRT6 regulation of ZEB1 deacetylation/degradation for EC–CLDN1 expression advances our understanding of diabetes-exacerbated atherosclerosis and provides a novel therapeutic target for intervention of diabetes-associated ASCVDs.
Article Highlights
SIRT6 downregulation in atherosclerotic vascular endothelial cells (ECs) is exacerbated under diabetic conditions, and EC-specific Sirt6 knockout aggravates diabetic atherosclerosis progression. EC-specific Sirt6 knockout aggravates atherosclerosis progression through vasculature hyperpermeability and monocyte/macrophage accumulation in vessels. SIRT6 directly interacts with transcription factor zinc finger E-box binding homeobox 1 (ZEB1) for deacetylation/degradation, preserving ZEB1 at a low level for normal expression of tight junction protein claudin-1 in ECs to maintain endothelial barrier function for vascular homeostasis. Naringin, a natural flavonoid ZEB1 inhibitor, reverses the diabetes-exacerbated vascular endothelial dysfunction to attenuate atherosclerosis progression, offering a promising, novel therapeutic strategy for diabetic atherosclerotic cardiovascular diseases.