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  3. 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

  • J Mol Cell Cardiol. 2022 Dec:173:154-168. doi: 10.1016/j.yjmcc.2022.10.009.
Siyi Wang 1,  Li Li 2,  Qingchun Liang 3,  Yuanzhi Ye 1,  Zirong Lan 1,  Qianqian Dong 1,  An Chen 1,  Mingwei Fu 1,  Yining Li 1,  Xiaoyu Liu 1,  Jing-Song Ou 4,  Lihe Lu 5,  Jianyun Yan 6
Affiliations

Affiliations

  • 1 Department of Cardiology, Laboratory of Heart Center, Heart Center, Zhujiang Hospital, Southern Medical University; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation; Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou 510280, China.
  • 2 Department of Cardiology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, China.
  • 3 Department of Anesthesiology, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510665, China.
  • 4 Division of Cardiac Surgery, National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, NHC key Laboratory of Assisted Circulation, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
  • 5 Department of Pathophysiolgy, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou 510080, China. Electronic address: [email protected].
  • 6 Department of Cardiology, Laboratory of Heart Center, Heart Center, Zhujiang Hospital, Southern Medical University; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation; Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou 510280, China. Electronic address: [email protected].
PMID: 36367517 DOI: 10.1016/j.yjmcc.2022.10.009
Abstract

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 vivo study 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.

Keywords

ATM; DNA damage; SIRT6; Vascular aging; Vascular calcification; Vascular smooth muscle cells.

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