Smooth Muscle Sirtuin 1 Blocks Thoracic Aortic Aneurysm/Dissection Development in Mice

Abstract

Purpose

Advancing age is the major risk factor for thoracic aortic aneurysm/dissection (TAAD). However, the causative link between age-related molecules and TAAD remains elusive. Here, we investigated the role of Sirtuin 1 (SIRT1, also known as class III histone deacetylase), the best studied member of the longevity-related Sirtuin family, in TAAD development in vivo.

Methods

We used male smooth muscle-specific SIRT1 transgenic (ST-Tg) mice, smooth muscle-specific SIRT1 knockout (ST-KO) mice, and their wild-type (WT) littermates on a C57BL/6J background to establish a TAAD model induced by oral administration of 3-aminopropionitrile fumarate (BAPN). We analyzed the incidence and fatality rates of TAAD in the groups. We examined matrix metallopeptidase 2 (MMP2) and MMP9 expression in aortas or cultured A7r5 cells via western blotting and real-time polymerase chain reaction (PCR). We performed chromatin immunoprecipitation (ChIP) to clarify the epigenetic mechanism of SIRT1-regulated MMP2 expression in vascular smooth muscle cells (VSMCs).

Results

BAPN treatment markedly increased the incidence of TAAD in WT mice but caused less disease in ST-Tg mice. Moreover, ST-KO mice had the highest BAPN-induced TAAD fatality rate of all the groups. Mechanistically, SIRT1 overexpression resulted in lower MMP2 and MMP9 expression after BAPN treatment in both mouse aortas and cultured A7r5 cells. The downregulation of BAPN-induced MMP2 expression by SIRT1 was mediated by deacetylation of histone H3 lysine 9 (H3K9) on the Mmp2 promoter in the A7r5 cells.

Conclusion

Our findings suggest that SIRT1 expression in SMCs protects against TAAD and could be a novel therapeutic target for TAAD management.

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Funding

This work was funded by grants from the National Natural Science Foundation of China (Numbers 81700411 and 91639110).

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Correspondence to Jinjing Liu or Jingang Zheng.

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Wang, F., Tu, Y., Gao, Y. et al. Smooth Muscle Sirtuin 1 Blocks Thoracic Aortic Aneurysm/Dissection Development in Mice. Cardiovasc Drugs Ther (2020). https://doi.org/10.1007/s10557-020-07005-w

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Keywords

  • Histone deacetylase
  • SIRT1
  • Vascular smooth muscle cell
  • Thoracic aortic aneurysm/dissection
  • Matrix metallopeptidase 2