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

Area of Science:

• Vascular biology
• Molecular mechanisms of aging
• Epigenetics

Background:

• Advancing age is a primary risk factor for thoracic aortic aneurysm/dissection (TAAD).
• The precise molecular links between aging and TAAD pathogenesis remain unclear.
• Sirtuin 1 (SIRT1), a longevity-associated protein, is implicated in cellular aging processes.

Purpose of the Study:

• To investigate the role of Sirtuin 1 (SIRT1) in the development of thoracic aortic aneurysm/dissection (TAAD).
• To elucidate the molecular mechanisms by which SIRT1 influences TAAD in vivo.

Main Methods:

• Utilized smooth muscle-specific SIRT1 transgenic (ST-Tg) and knockout (ST-KO) mice, alongside wild-type (WT) littermates.
• Induced TAAD using 3-aminopropionitrile fumarate (BAPN) and assessed incidence and fatality rates.
• Quantified matrix metallopeptidase 2 (MMP2) and MMP9 expression and investigated SIRT1's epigenetic regulation of MMP2 via chromatin immunoprecipitation (ChIP).

Main Results:

• BAPN treatment increased TAAD incidence in WT mice, with reduced incidence in ST-Tg mice and the highest fatality rate in ST-KO mice.
• SIRT1 overexpression led to decreased MMP2 and MMP9 expression following BAPN treatment in both mouse aortas and cultured cells.
• SIRT1 downregulated BAPN-induced MMP2 expression by deacetylating histone H3 lysine 9 (H3K9) on the Mmp2 promoter.

Conclusions:

• SIRT1 expression in smooth muscle cells confers protection against TAAD.
• SIRT1 acts by suppressing MMP2 and MMP9 expression, crucial in TAAD development.
• SIRT1 represents a potential therapeutic target for managing TAAD.