Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1.
Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1.
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DOI：
10.18632/oncotarget.9687
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发表时间：
2016-06-28
期刊：
影响因子：
--
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Bai B;Man AW;Yang K;Guo Y;Xu C;Tse HF;Han W;Bloksgaard M;De Mey JG;Vanhoutte PM;Xu A;Wang Y
Aims-SIRT 1对细胞衰老和血管老化发挥有效的活性。通过降低LKB 1蛋白水平，它促进了内皮细胞的存活和再生。本研究旨在探讨SIRT 1介导的LKB 1降解预防血管老化的分子机制。方法和结果-免疫共沉淀试验表明，SIRT 1，通过其氨基末端，结合到DOC结构域的HERC 2 [HECT和RLD结构域包含E3泛素蛋白连接酶2]，然后泛素化LKB 1在内皮细胞的核室。定点突变显示LKB 1的赖氨酸（K）64处的乙酰化触发SIRT 1/HERC 2/LKB 1蛋白复合物的形成和随后的蛋白酶体降解。体外细胞研究表明，乙酰化LKB 1在细胞核中的积累导致内皮细胞活化，进而刺激血管平滑肌细胞的增殖和细胞外基质蛋白的产生。染色质免疫沉淀定量PCR证实乙酰化的LKB 1与TGFβ1启动子相互作用并激活TGFβ1启动子，而SIRT 1抑制该启动子。SIRT 1或HERC 2的敲除导致LKB 1与TGFβ1启动子的正调控元件的结合增加。在没有内皮型一氧化氮合酶的小鼠中，内皮细胞中选择性过表达人SIRT 1可预防高血压和年龄相关的不良动脉重塑。慢病毒介导的HERC 2敲低消除了内皮SIRT 1对动脉重塑和动脉血压控制的有益作用。结论-通过HERC 2下调乙酰化LKB 1蛋白，SIRT 1微调内皮细胞和血管平滑肌细胞之间的串扰，以防止不良动脉重塑和维持血管稳态。
Aims-SIRT1 exerts potent activity against cellular senescence and vascular ageing. By decreasing LKB1 protein levels, it promotes the survival and regeneration of endothelial cells. The present study aims to investigate the molecular mechanisms underlying SIRT1-mediated LKB1 degradation for the prevention of vascular ageing. Methods and Results-Co-immunoprecipitation assay demonstrated that SIRT1, via its amino-terminus, binds to the DOC domain of HERC2 [HECT and RLD domain containing E3 ubiquitin protein ligase 2], which then ubiquitinates LKB1 in the nuclear compartment of endothelial cells. Site-directed mutagenesis revealed that acetylation at lysine (K) 64 of LKB1 triggers the formation of SIRT1/HERC2/LKB1 protein complex and subsequent proteasomal degradation. In vitro cellular studies suggested that accumulation of acetylated LKB1 in the nucleus leads to endothelial activation, in turn stimulating the proliferation of vascular smooth muscle cells and the production of extracellular matrix proteins. Chromatin immunoprecipitation quantitative PCR confirmed that acetylated LKB1 interacts with and activates TGFβ1 promoter, which is inhibited by SIRT1. Knocking down either SIRT1 or HERC2 results in an increased association of LKB1 with the positive regulatory elements of TGFβ1 promoter. In mice without endothelial nitric oxide synthase, selective overexpression of human SIRT1 in endothelium prevents hypertension and age-related adverse arterial remodeling. Lentiviral-mediated knockdown of HERC2 abolishes the beneficial effects of endothelial SIRT1 on both arterial remodeling and arterial blood pressure control. Conclusion-By downregulating acetylated LKB1 protein via HERC2, SIRT1 fine-tunes the crosstalk between endothelial and vascular smooth muscle cells to prevent adverse arterial remodeling and maintain vascular homeostasis.
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影响因子：
7.3
作者：
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通讯作者：
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影响因子：
64.8
作者：
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1.6
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
56.9
作者：
LANGILLE, BL;ODONNELL, F
通讯作者：
ODONNELL, F