SIRT6 inhibits cholesterol crystal-induced vascular endothelial dysfunction via Nrf2 activation
| Autor: | Zihan Zheng, Hongqian Gao, Rong Lin, Yanhao He, Feng Yao, Bo Wang, Weirong Wang, Zhen Jin, Lifang Chen, Xiaohan Lv, Yunfang Xiao |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
SIRT6 Male medicine.medical_specialty Nitric Oxide Synthase Type III NF-E2-Related Factor 2 Hyperlipidemias Biology Nitric Oxide Nitric oxide 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Downregulation and upregulation Enos Internal medicine medicine Human Umbilical Vein Endothelial Cells Animals Humans Sirtuins Endothelial dysfunction Cells Cultured Cell adhesion molecule Cholesterol Cell Biology biology.organism_classification medicine.disease Atherosclerosis 030104 developmental biology Endocrinology chemistry 030220 oncology & carcinogenesis Sirtuin biology.protein Female Endothelium Vascular |
| Zdroj: | Experimental cell research. 387(1) |
| ISSN: | 1090-2422 |
| Popis: | Sirtuin 6 (SIRT6), a nicotinamide adenine dinucleotide-dependent deacetylase, participates in various age-related disorders, such as dyslipidemia and cardiovascular diseases. Recent studies have revealed that minute cholesterol crystals (CCs), which are generated after excess free cholesterol accumulation, form not only in mature atherosclerotic plaques but also extremely early in atherosclerosis. Since endothelial dysfunction is an early feature of atherogenesis, this study was designed to investigate the role of SIRT6 in minute CC-induced endothelial dysfunction and the related mechanism. We found that minute CCs could be endocytosed by endothelial cells (ECs), which then decreased nitric oxide (NO) levels and endothelial nitric oxide synthase (eNOS) activity and expression, upregulated the expression of adhesion molecules and enhanced monocyte adhesion to ECs. In addition, minute CCs significantly suppressed SIRT6 expression in ECs. Moreover, the overexpression of SIRT6 could mitigate minute CC-induced endothelial dysfunction. In addition, the expression of Nuclear factor erythroid2-related factor2 (Nrf2) was suppressed after minute CC treatment, whereas SIRT6 overexpression reversed this decrease in Nrf2 expression. More importantly, Nrf2 activation also notably attenuated minute CC-induced endothelial dysfunction. In vivo experiments further indicated that endothelium-specific SIRT6 depletion impaired vascular endothelial function and suppressed Nrf2 expression in hyperlipidemic mice. Taken together, these results indicate that SIRT6 rescues minute CC-induced endothelial dysfunction partly via Nrf2 activation. |
| Databáze: | OpenAIRE |
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