Deletion of SIRT6 in vascular smooth muscle cells facilitates vascular calcification via suppression of DNA damage repair
Deletion of SIRT6 in vascular smooth muscle cells facilitates vascular calcification via suppression of DNA damage repair
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血管平滑肌细胞中 SIRT6 的缺失通过抑制 DNA 损伤修复促进血管钙化
DOI：
10.1016/j.yjmcc.2022.10.009
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Jianyun Yan
中科院分区：
文献类型：
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作者：
Siyi Wang;Li Li;Qingchun Liang;Yuanzhi Ye;Zirong Lan;Qianqian Dong;An Chen;Mingwei Fu;Yining Li;Xiaoyu Liu;Jingsong Ou;Lihe Lu;Jianyun Yan
血管钙化是心血管事件的重要危险因素，在此过程中伴随着DNA损伤。sirtuin 6（SIRT 6）具有减轻动脉粥样硬化的作用，这与减少DNA损伤有关。然而，平滑肌细胞SIRT 6是否介导涉及DNA损伤的血管钙化仍不清楚。Western blot和免疫荧光显示，SIRT 6在人血管平滑肌细胞（HVSMCs），人和小鼠动脉血管钙化过程中的表达下降。茜素红染色和钙含量测定结果显示，SIRT 6基因敲除或缺失可显著促进高磷、高钙诱导的HVSMC钙化，并伴有成骨分化标志物Runx 2和BMP 2表达上调。相反，腺病毒介导的SIRT 6过表达减弱了HVSMC的成骨分化和钙化。此外，体外研究表明，SIRT 6过表达抑制小鼠和人类动脉环的钙化。值得注意的是，平滑肌细胞特异性敲除SIRT 6显著加重了维生素D3诱导的小鼠主动脉钙化。从机制上讲，SIRT 6的过表达减少了HVSMCs钙化过程中的DNA损伤并上调了p-ATM，而SIRT 6的敲低则表现出相反的效果。HVSMCs中ATM的敲低废除了SIRT 6过表达对钙化和DNA损伤的抑制作用。这项研究首次证明，血管平滑肌细胞特异性SIRT 6缺失通过抑制DNA损伤修复促进血管钙化。因此，SIRT 6和DNA损伤修复的调节可能代表血管钙化的治疗策略。
Vascular calcification is an important risk factor for cardiovascular events, accompanied by DNA damage during the process. The sirtuin 6 (SIRT6) has been reported to alleviate atherosclerosis, which is related to the reduction of DNA damage. However, whether smooth muscle cell SIRT6 mediates vascular calcification involving DNA damage remains unclear. Western blot and immunofluorescence revealed that SIRT6 expression was decreased in human vascular smooth muscle cells (HVSMCs), human and mouse arteries during vascular calcification. Alizarin red staining and calcium content assay showed that knockdown or deletion of SIRT6 significantly promoted HVSMC calcification induced by high phosphorus and calcium, accompanied by upregulation of osteogenic differentiation markers including Runx2 and BMP2. By contrast, adenovirus-mediated SIRT6 overexpression attenuated osteogenic differentiation and calcification of HVSMCs. Moreover,ex vivostudy revealed that SIRT6 overexpression inhibited calcification of mouse and human arterial rings. Of note, smooth muscle cell-specific knockout of SIRT6 markedly aggravated Vitamin D3-induced aortic calcification in mice. Mechanistically, overexpression of SIRT6 reduced DNA damage and upregulated p-ATM during HVSMCs calcification, whereas knockdown of SIRT6 showed the opposite effects. Knockdown of ATM in HVSMCs abrogated the inhibitory effect of SIRT6 overexpression on calcification and DNA damage. This study for the first time demonstrates that vascular smooth muscle cell-specific deletion of SIRT6 facilitates vascular calcification via suppression of DNA damage repair. Therefore, modulation of SIRT6 and DNA damage repair may represent a therapeutic strategy for vascular calcification.